US 20170210797A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0210797 A1 Kretz-ROmmel et al. (43) Pub. Date: Jul. 27, 2017
(54) ANTIBODIES THAT BIND HUMAN Publication Classification CANNABINOID 1 (CB1) RECEPTOR (51) Int. Cl. (71) Applicant: BIRD ROCK BIO, INC., La Jolla, CA C07K 6/28 (2006.01) (US) (52) U.S. Cl. (72) Inventors: Anke Kretz-Rommel, San Diego, CA CPC ...... C07K 16/28 (2013.01); A61K 47/48561 (US); Lei Shi, Shanghai (CN); Roger (2013.01); C07K 231 7/565 (2013.01); C07K Ferrini, Solana Beach, CA (US); Teddy 231 7/56 (2013.01); C07K 2317/52 (2013.01); Yang, Shanghai (CN); Fei Xu, Palm C07K 2317/92 (2013.01); C07K 2317/24 Beach Gardens, FL (US); Brian (2013.01); C07K 2317/732 (2013.01); C07K Campion, La Jolla, CA (US) 2317/734 (2013.01); A61K 2039/505 (2013.01) (21) Appl. No.: 14/774,582 (22) PCT Filed: Mar. 27, 2015 (57) ABSTRACT (86). PCT No.: PCT/US2O15/023108 The present invention relates to novel antibodies and frag S 371 (c)(1), ments thereof that binds cannabinoid 1 (CB1) receptor. The (2) Date: Sep. 10, 2015 antibodies and fragments thereofas disclosed herein include (30) Foreign Application Priority Data humanized antibodies that bind CB1 receptor. The invention also includes uses of the antibodies for treating a disease or Mar. 27, 2014 (CN) ...... PCT/CN2014/0741.99 disorder responsive to antagonism or agonism of the CB1 Jul. 8, 2014 (CN) ...... PCT/CN2014/081797 receptor. Patent Application Publication Jul. 27, 2017. Sheet 1 of 66 US 2017/0210797 A1
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S- SS Yxx-SwsŠ.S s KŠ & S. -SSS s s S. Š$ SSSSSSSSSSSS is sysssssss ex - s s S. S. SS- S w s anti-IIs issosS & S. oil looooooooo A canc. (Egil a tiss Ritxistia anti-HEL higo , io do looo loooo Ab cone. (agni FG, 22A Patent Application Publication Jul. 27, 2017. Sheet 54 of 66 US 2017/0210797 A1 aii ses: 40 20 , , S. s A cone, (tig m. it wSt. ss ' s & sererrestereyrresperers . , is, At eane. (ug in FG Patent Application Publication Jul. 27, 2017. Sheet 55 of 66 US 2017/0210797 A1 si xS sists ŠSS. &ssyhigG odou ool or i to 100 eese. rig is six is & SSSSSSsssss SSSSS sSass ^ss S, s. , s At cone. (signal FG. 22C Patent Application Publication Jul. 27, 2017. Sheet 56 of 66 US 2017/0210797 A1 Daudi & Ritxi rab Š anti-HEL-higG sts 8 ww. xx sasayus S&N t1 . . O. 1 conc. ign Daudi 6 PC4-H2-igG2 & anti-HEL-higG2 i 3 S 1. a 5 0.00 O.O. 0. 1 10 OO Conc. Ign aidi 85 6. & PC4H2-ig64. i & anti-HEi-hig34. . , . 1. conc. girai FG. 22 D Patent Application Publication Jul. 27, 2017. 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SF see r S f a. & w ea st ce a n -- supe r w E is 8 ex: ur ri s & O s s ck k.is Eë as a ts a a to & s & its ...... is a ge. e. e. e. ere Otto O. C. Patent Application Publication Jul. 27, 2017. Sheet 66 of 66 US 2017/0210797 A1 ;---&~~~~-~~~~);· ; ories to US 2017/0210797 A1 Jul. 27, 2017 ANTIBODIES THAT BIND HUMAN receptor signaling activity. In some embodiments, the CB1 CANNABINOID 1 (CB1) RECEPTOR receptor binding antibodies or fragments thereof are ago nistic antibodies, in that they enhance CB1 receptor signal CROSS-REFERENCE TO RELATED ing activity. In some embodiments, the CB1 receptor bind APPLICATIONS ing antibodies or fragments thereof are modulators of CB1 receptor signaling activity or are allosteric modulators of 0001. This application claims priority to International CB1 receptor signaling activity. In some embodiments the Application No. PCT/CN2014/074199, filed Mar. 27, 2014, CB1 receptor binding antibodies or fragments thereof are and International Application No. PCT/CN2014/081797, selective binders without agonist or antagonist activity. In filed Jul. 8, 2014, which are incorporated herein by reference some embodiments, the CB1 receptor binding antibodies or in their entireties. fragments thereof are selective binders without agonist or antagonist activity that are useful for diagnostic and/or FIELD OF THE INVENTION imaging purposes. 0002 The present invention relates to antibodies and 0007. The isolated antibodies or antigen binding frag antigen-binding fragments thereof that bind to cannabinoid ments thereof, in Some embodiments, are at least as potent receptor 1 (CB1) receptor, and methods of using Such as small molecule CB1 receptor modulators such as, for antibodies and antigen-binding fragments. example, AM6545, AM251, or rimonabant. In some embodiments, the antibodies or fragments thereof have CB1 DESCRIPTION OF THE TEXT FILE receptor inhibiting or activating activity that is at least 2 SUBMITTED ELECTRONICALLY fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 10 0003. The contents of the text file submitted electroni fold, or at least 20 fold more potent relative to the small cally herewith are incorporated herein by reference in their molecules AM6545, AM251, or rimonabant. In some entirety: A computer readable format copy of the Sequence embodiments, the isolated antibodies or antigen binding Listing (filename: 15-343-WO3-Seq List ST25.txt, date fragments thereof inhibit CB1 receptor agonist-mediated recorded: Mar. 27, 2015, file size 793 KB). signal transduction. In some embodiments, the inhibition of CB1 receptor agonist-mediated signal transduction is mea BACKGROUND sured by determining intracellular cAMP levels and/or downstream ERK phosphorylation. 0004 Cannabinoid 1 (CB1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily. The CB1 0008. In some embodiments, the isolated antibodies and receptor is expressed in the central nervous system (CNS), antigen-binding fragments thereof have the advantage of lungs, liver, adipose tissue and kidneys, and has been reduced or absent brain penetration. In some embodiments, implicated in many human diseases including obesity, dia the brain penetration of the isolated antibodies and antigen betes, fibrosis, liver diseases, cardiovascular disease, cancer, binding fragments thereof exhibit reduced brain penetration pain, MS spasticity, and glaucoma, among others. More relative to Small molecule CB1 receptor agonists or antago specifically, CB1 receptor has been shown to exhibit detri nists (e.g., AM6545, AM251, or rimonabant). In some mental activity in, for example, obesity, diabetes, fibrosis, embodiments, the CB1 receptor binding antibodies and liver diseases, cardiovascular disease and cancer; and has fragments thereof provided herein provide a therapeutic been shown to exhibit beneficial activity in pain, MS spas benefit with reduced central nervous system side effects ticity and glaucoma, among others. relative to a small molecule CB1 receptor agonist or antago 0005. There is a need in the art for new CB1 receptor nist. CNS side effects associated with small molecule CB1 antagonists and agonists for therapeutic purposes as well as receptor antagonist rimonabant include anxiety, depression, selective binders for diagnostic/imaging purposes. In par agitation, eating disorders, irritability, aggression, and ticular, a CB1 receptor-targeting compound that lacks the insomnia (Moreira, 2009, Rev Bras Psiquiatr., 31(2): 145 capacity for CNS penetration would be desirable to reduce 53). potential CNS-mediated side effects of CB1 receptor modu 0009. In some embodiments, the isolated antibodies and lation, highlighted by the psychiatric adverse events asso antigen-binding fragments thereof provided herein are gen ciated with the CB1 inverse agonist rimonabant. erated from hybridoma cell lines. In other embodiments, the isolated antibodies and antigen-binding fragments thereof SUMMARY OF THE INVENTION provided herein are generated from phage display libraries. 0006. In one aspect, the present invention provides anti 0010. In some embodiments, the isolated antibodies and bodies and antigen-binding fragments thereof that bind to antigen-binding fragments thereof provided herein have an cannabinoid 1 receptor (also referred to herein as “CB1 affinity for native human CB1 receptor that is at least nM receptor or “CB1). In some embodiments, the CB1 recep range. For example, in some embodiments, the affinity for tor is a human CB1 receptor. In some embodiments, the CB1 receptor is about 1 uM or less, or about 750 nM or less, antibody or fragment thereof recognizes one or more extra or about 500 nM or less, or about 250 nM or less, or about cellular epitopes on the CB1 receptor. In some embodi 100 nM or less, or about 75 nM or less, or about 50 nM or ments, the CB1 receptor binding antibodies and fragments less, or about 25 nM or less, or about 10 nM or less, or about thereof provided herein are functional antibodies or antigen 1 nM or less. In some embodiments, the isolated antibodies binding fragments thereof. In some embodiments, the CB1 and antigen-binding fragments thereof have an affinity for receptor binding antibodies or fragments thereof inhibit or human CB1 receptor that is from about 0.01 nM to about 500 increase CB1 receptor signaling activity. In some embodi nM, about 0.02 nM to about 250 nM, about 0.02 to about ments, the CB1 receptor binding antibodies or fragments 200 nM, about 0.05 to about 100 nM, about 0.05 to about 50 thereof are antagonistic antibodies, in that they inhibit CB1 nM. US 2017/0210797 A1 Jul. 27, 2017 0011. The isolated antibodies and antigen binding frag ing to SEQ ID NO: 1; a heavy chain constant region ments thereof of the present invention may be derived from comprising a nucleic acid sequence according to SEQ ID any species including, but not limited to, mouse, rat, rabbit, NO: 3; a light chain variable region comprising a nucleic hamster, guinea pig, primate, llama or human. In some acid sequence according to SEQID NO: 5; and a light chain embodiments, the isolated antibodies and antigen binding constant region comprising a nucleic acid sequence accord fragments thereof are murine antibodies. In other embodi ing to SEQ ID NO: 7. ments, the isolated antibodies and antigenbinding fragments 0015. In one embodiment, the isolated antibody or anti thereof are chimeric antibodies. In still other embodiments, gen binding fragment thereof comprises a heavy chain the isolated antibodies and antigen binding fragments variable region comprising an amino acid sequence accord thereofare humanized antibodies. In some embodiments, the ing to SEQ ID NO: 2; a heavy chain constant region isolated antibodies and antigen binding fragments thereof comprising an amino acid sequence according to SEQ ID are fully human antibodies. NO: 4; a light chain variable region comprising an amino 0012. In one embodiment, the isolated antibodies and acid sequence according to SEQID NO: 6; and a light chain antigen binding fragments thereof are humanized or chime constant region comprising an amino acid sequence accord ric P1C4 antibodies, as described herein. In one embodi ing to SEQ ID NO: 8. ment, the humanized P1C4 antibodies are selected from the 0016. In one embodiment, the isolated antibody or anti group consisting of P1C4-HO, P1C4-H2, and P1C4-H4, as gen binding fragment thereof comprises a heavy chain described herein. In one embodiment, the isolated antibodies variable region comprising a nucleic acid sequence accord and antigen binding fragments thereof comprise Fc modifi ing to SEQ ID NO: 9; a heavy chain constant region cations that result in reduced, impaired, or eliminated anti comprising a nucleic acid sequence according to SEQ ID body effector function. In a further embodiment, the isolated NO: 11; a light chain variable region comprising a nucleic antibodies and antigen binding fragments thereof are acid sequence according to SEQ ID NO: 13; and a light selected from the group consisting of P1C4-HO-IgG2-4 chain constant region comprising a nucleic acid sequence according to SEQ ID NO: 15. 0017. In one embodiment, the isolated antibody or anti gen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence accord ing to SEQ ID NO: 10; a heavy chain constant region 0013 In one embodiment, the isolated antibody or anti comprising an amino acid sequence according to SEQ ID gen binding fragment thereof comprises a heavy chain NO: 12; a light chain variable region comprising an amino variable region comprising a nucleic acid sequence selected acid sequence according to SEQ ID NO: 14; and a light from the group consisting of SEQ ID NOS. 1, 9, 17, 25, 33, chain constant region comprising an amino acid sequence 41, 49, and 57. In another embodiment, the isolated antibody according to SEQ ID NO: 16. or antigenbinding fragment thereof comprises a heavy chain 0018. In one embodiment, the isolated antibody or anti variable region comprising an amino acid sequence selected gen binding fragment thereof comprises a heavy chain from the group consisting of SEQID NOS. 2, 10, 18, 26, 34, variable region comprising a nucleic acid sequence accord 42, 50, and 58. In another embodiment, the isolated antibody ing to SEQ ID NO: 17; a heavy chain constant region or antigenbinding fragment thereof comprises a heavy chain comprising a nucleic acid sequence according to SEQ ID constant region comprising a nucleic acid sequence selected NO: 19; a light chain variable region comprising a nucleic from the group consisting of SEQID NOS. 3, 11, 19, 27, 35, acid sequence according to SEQ ID NO: 21; and a light 43, 51, and 59. In another embodiment, the isolated antibody chain constant region comprising a nucleic acid sequence or antigenbinding fragment thereof comprises a heavy chain according to SEQ ID NO. 23. constant region comprising an amino acid sequence selected 0019. In one embodiment, the isolated antibody or anti from the group consisting of SEQID NOS. 4, 12, 20, 28, 36, gen binding fragment thereof comprises a heavy chain 44, 52, and 60. In another embodiment, the isolated antibody variable region comprising an amino acid sequence accord or antigen binding fragment thereof comprises a light chain ing to SEQ ID NO: 18; a heavy chain constant region variable region comprising a nucleic acid sequence selected comprising an amino acid sequence according to SEQ ID from the group consisting of SEQID NOs 5, 13, 21, 29, 37, NO. 20; a light chain variable region comprising an amino 45, 53, and 61. In another embodiment, the isolated antibody acid sequence according to SEQ ID NO: 22; and a light or antigen binding fragment thereof comprises a light chain chain constant region comprising an amino acid sequence variable region comprising an amino acid sequence selected according to SEQ ID NO: 24. from the group consisting of SEQID NOS. 6, 14, 22, 30, 38. 0020. In one embodiment, the isolated antibody or anti 46, 54, and 62. In another embodiment, the isolated antibody gen binding fragment thereof comprises a heavy chain or antigen binding fragment thereof comprises a light chain variable region comprising a nucleic acid sequence accord constant region comprising an amino acid sequence selected ing to SEQ ID NO: 25; a heavy chain constant region from the group consisting of SEQID NOS. 7, 15, 23, 31, 39, comprising a nucleic acid sequence according to SEQ ID 47, 55, and 63. In another embodiment, the isolated antibody NO: 27; a light chain variable region comprising a nucleic or antigen binding fragment thereof comprises a light chain acid sequence according to SEQ ID NO: 29; and a light constant region comprising an amino acid sequence selected chain constant region comprising a nucleic acid sequence from the group consisting of SEQID NOS. 8, 16, 24, 32, 40, according to SEQ ID NO: 31. 48, 56, and 64. 0021. In one embodiment, the isolated antibody or anti 0014. In one embodiment, the isolated antibody or anti gen binding fragment thereof comprises a heavy chain gen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence accord variable region comprising a nucleic acid sequence accord ing to SEQ ID NO: 26; a heavy chain constant region US 2017/0210797 A1 Jul. 27, 2017 comprising an amino acid sequence according to SEQ ID NO. 59; a light chain variable region comprising a nucleic NO: 28; a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 61; and a light acid sequence according to SEQ ID NO:30; and a light chain constant region comprising a nucleic acid sequence chain constant region comprising an amino acid sequence according to SEQ ID NO: 63. according to SEQ ID NO: 32. 0029. In one embodiment, the isolated antibody or anti 0022. In one embodiment, the isolated antibody or anti gen binding fragment thereof comprises a heavy chain gen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence accord variable region comprising a nucleic acid sequence accord ing to SEQ ID NO: 58; a heavy chain constant region ing to SEQ ID NO: 33; a heavy chain constant region comprising an amino acid sequence according to SEQ ID comprising a nucleic acid sequence according to SEQ ID NO: 60; a light chain variable region comprising an amino NO:35; a light chain variable region comprising a nucleic acid sequence according to SEQ ID NO: 62; and a light acid sequence according to SEQ ID NO: 37; and a light chain constant region comprising an amino acid sequence chain constant region comprising a nucleic acid sequence according to SEQ ID NO: 64. according to SEQ ID NO: 39. 0023. In one embodiment, the isolated antibody or anti 0030. In one embodiment, the invention provides an gen binding fragment thereof comprises a heavy chain isolated antibody or fragment thereof that comprises a variable region comprising an amino acid sequence accord nucleic acid sequence or an amino acid sequence that is at ing to SEQ ID NO. 34: a heavy chain constant region least 65%, at least 70%, at least 75%, at least 80%, at least comprising an amino acid sequence according to SEQ ID 85%, at least 90%, at least 95%, or at least 99% identical to NO: 36; a light chain variable region comprising an amino an amino acid sequence selected from the group consisting acid sequence according to SEQ ID NO: 38; and a light of SEQ ID NOs. 1-351. chain constant region comprising an amino acid sequence 0031. In one embodiment, the isolated antibody or anti according to SEQ ID NO: 40. gen binding fragment thereof comprises heavy chain 0024. In one embodiment, the isolated antibody or anti complementary determining regions (CDRS) independently gen binding fragment thereof comprises a heavy chain selected from the CDRs present in the heavy chain variable variable region comprising a nucleic acid sequence accord regions according to SEQ ID NOS: 2, 10, 18, and 26. In ing to SEQ ID NO: 41; a heavy chain constant region another embodiment, the isolated antibody or antigen bind comprising a nucleic acid sequence according to SEQ ID ing fragment thereof comprises light chain CDRS indepen NO: 43; a light chain variable region comprising a nucleic dently selected from the CDRs present in the light chain acid sequence according to SEQ ID NO: 45; and a light variable regions according to SEQ ID NOS: 6, 14, 22, and chain constant region comprising a nucleic acid sequence 3O. according to SEQ ID NO: 47. 0032. In one embodiment, the isolated antibody or anti 0025. In one embodiment, the isolated antibody or anti gen binding fragment thereof is a humanized antibody gen binding fragment thereof comprises a heavy chain comprising heavy chain complementary determining variable region comprising an amino acid sequence accord regions (CDRs) independently selected from the CDRs ing to SEQ ID NO: 42; a heavy chain constant region present in the heavy chain variable regions according to comprising an amino acid sequence according to SEQ ID SEQID NOS: 2, 10, 18, and 26. In another embodiment, the NO: 44; a light chain variable region comprising an amino isolated antibody or antigen binding fragment thereof is a acid sequence according to SEQ ID NO: 46; and a light humanized antibody comprising light chain complementary chain constant region comprising an amino acid sequence determining regions (CDRs) independently selected from according to SEQ ID NO: 48. the CDRs present in the light chain variable regions accord 0026. In one embodiment, the isolated antibody or anti ing to SEQ ID NOS: 6, 14, 22, and 30. gen binding fragment thereof comprises a heavy chain 0033. In one embodiment, the heavy chain variable variable region comprising a nucleic acid sequence accord region comprises, consists essentially of, or consists of an ing to SEQ ID NO: 49; a heavy chain constant region amino acid sequence selected from the group consisting of comprising a nucleic acid sequence according to SEQ ID SEQ ID NOs: 339-341. In one embodiment, the isolated NO: 51; a light chain variable region comprising a nucleic antibody or antigen binding fragment thereof comprises a acid sequence according to SEQ ID NO: 53; and a light heavy chain variable region amino acid sequence that is at chain constant region comprising a nucleic acid sequence least 65%, at least 70%, at least 75%, at least 80%, at least according to SEQ ID NO: 55. 85%, at least 90%, at least 95%, at least 96%, at least 97%, 0027. In one embodiment, the isolated antibody or anti at least 98% or at least 99% identical to an amino acid gen binding fragment thereof comprises a heavy chain sequence selected from the group consisting of SEQ ID variable region comprising an amino acid sequence accord NOs: 339-341. In a further embodiment, the heavy chain ing to SEQ ID NO: 50; a heavy chain constant region variable region comprises, consists essentially of, or consists comprising an amino acid sequence according to SEQ ID of an amino acid sequence selected from the group consist NO. 52; a light chain variable region comprising an amino ing of SEQ ID NOs: 339-341. acid sequence according to SEQ ID NO: 54; and a light 0034. In another embodiment, the isolated antibody or chain constant region comprising an amino acid sequence antigen binding fragment thereof comprises a heavy chain according to SEQ ID NO: 56. amino acid sequence that is least 65%, at least 70%, at least 0028. In one embodiment, the isolated antibody or anti 75%, at least 80%, at least 85%, at least 90%, at least 95%, gen binding fragment thereof comprises a heavy chain at least 96%, at least 97%, at least 98% or at least 99% variable region comprising a nucleic acid sequence accord identical to an amino acid sequence selected from the group ing to SEQ ID NO: 57; a heavy chain constant region consisting of SEQ ID NOs: 343-351. In a further embodi comprising a nucleic acid sequence according to SEQ ID ment, the heavy chain comprises, consists essentially of, or US 2017/0210797 A1 Jul. 27, 2017 consists of an amino acid sequence selected from the group isolated antibody or fragment thereof comprises a light chain consisting of SEQ ID NOS:343-351. CDR3 sequence having at least 80%, at least 85%, at least 0035. In another embodiment, the isolated antibody or 90%, at least 95% at least 96%, at least 97%, at least 98%, antigen binding fragment thereof comprises a light chain or at least 99% homology to the amino acid sequence of variable region amino acid sequence that is least 65%, at SEQ ID NO:357 (HQYHRSPPTF). least 70%, at least 75%, at least 80%, at least 85%, at least 0038. In one embodiment, the isolated antibody or anti 90%, at least 95%, at least 96%, at least 97%, at least 98% gen binding fragment thereof comprises a heavy chain or at least 99% identical to an amino acid sequence accord CDR1, CDR2, and CDR3 comprising amino acid sequences ing to SEQID NO:337. In a further embodiment, the heavy according to SEQ ID NOS: 352, 353, and 354, respectively. chain variable region comprises, consists essentially of, or In another embodiment, the isolated antibody or antigen consists of an amino acid sequence according to SEQ ID binding fragment thereof comprises a light chain CDR1. NO: 337. In another embodiment, the isolated antibody or CDR2, and CDR3 comprising amino acid sequences accord antigen binding fragment thereof comprises a light chain ing to SEQ ID NOs: 355, 356, and 357, respectively. In a amino acid sequence that is least 65%, at least 70%, at least further embodiment, the isolated antibody or antigen bind 75%, at least 80%, at least 85%, at least 90%, at least 95%, ing fragment thereof comprises a heavy chain CDR1, heavy at least 96%, at least 97%, at least 98% or at least 99% chain CDR2, heavy chain CDR3, light chain CDR1, light identical to an amino acid sequence according to SEQ ID chain CDR2, and light chain CDR3 comprising amino acid NO: 338. In a further embodiment, the light chain com sequences according to SEQ ID NOS: 352, 353, 354, 355, prises, consists essentially of, or consists of an amino acid 356, and 357, respectively. In a still further embodiment, the sequence according to SEQ ID NO: 338. isolated antibody or fragment thereof is chimeric or human 0036. In one embodiment, the invention provides a ized. humanized isolated antibody or antigen binding fragment 0039. The person of skill in the art will understand that thereofthat binds CB1. In a further embodiment, the isolated the heavy and light chain CDRs of the antibodies provided antibody or antigen binding fragment thereof comprises a herein may be independently selected, or mixed and light chain variable region according to SEQ ID NO: 337 matched, to form an antibody or binding fragment thereof and a heavy chain variable region according to SEQID NO: comprising any light chain CDR1, CDR2, and CDR3; and 339. In another embodiment, the isolated antibody or anti any heavy chain CDR1, CDR2, and CDR3 from the anti gen binding fragment thereof comprises a light chain vari bodies provided herein. The skilled person will further able region according to SEQID NO:337 and a heavy chain understand that the heavy and light chain variable regions of variable region according to SEQ ID NO: 340. In another the antibodies provided herein may be independently embodiment, the isolated antibody or antigen binding frag selected, or mixed and matched, to form an antibody or ment thereof comprises a light chain variable region accord binding fragment comprising any heavy and light chain from ing to SEQ ID NO: 337 and a heavy chain variable region the antibodies provided herein. according to SEQID NO: 341. In another embodiment, the 0040. In one embodiment, the antibody or antigen bind isolated antibody or antigen binding fragment thereof com ing fragment thereof provided herein is a chimeric antibody prises a full light chain according to SEQ ID NO: 338 and or fragment containing heavy and light chain CDRS selected a full heavy chain according to a sequence selected from the from the CDRs provided herein, or conservative variants of group consisting of SEQ ID NOs: 343-351. the CDRs provided herein. In another embodiment, the 0037. In one embodiment, the isolated antibody or frag antibody or antigen binding fragment thereof provided ment thereof comprises a heavy chain CDR1 sequence herein is a humanized antibody or fragment containing having at least 80%, at least 85%, at least 90%, at least 95% heavy and light chain CDRs selected from the CDRs pro at least 96%, at least 97%, at least 98%, or at least 99% vided herein, or conservative variants of the CDRs provided homology to the amino acid sequence of SEQ ID NO: 352 herein. In one embodiment, the antibody or antigen binding (YYWMN). In another embodiment, the isolated antibody fragment thereof provided herein comprises a light chain or fragment thereof comprises a heavy chain CDR2 and/or a heavy chain comprising a sequence provided sequence having at least 80%, at least 85%, at least 90%, at herein, or a conservative variant thereof. In one embodi least 95% at least 96%, at least 97%, at least 98%, or at least ment, the conservative variants have at least 80%, at least 99% homology to the amino acid sequence of SEQ ID NO: 85%, at least 90%, at least 95%, at least 96%, at least 97%, 353 (QIYPGDGETKY). In another embodiment, the iso at least 98% or at least 99% homology to the reference lated antibody or fragment thereof comprises a heavy chain sequence provided herein. In one embodiment, the conser CDR3 sequence having at least 80%, at least 85%, at least vative variants comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more 90%, at least 95% at least 96%, at least 97%, at least 98%, amino acid Substitutions, insertions, or deletions. or at least 99% homology to the amino acid sequence of 0041. In some embodiments, the isolated antibody or SEQ ID NO: 354 (SHGNYLPY). In another embodiment, antigen binding fragment thereof binds CB1 and exhibits the isolated antibody or fragment thereof comprises a light reduced effector function. In one embodiment, the isolated chain CDR1 sequence having at least 80%, at least 85%, at antibody or antigen binding fragment thereof binds CB1 and least 90%, at least 95% at least 96%, at least 97%, at least comprises one or more Fc region modifications. In a further 98%, or at least 99% homology to the amino acid sequence embodiment, the antibody or antigen binding fragment of SEQ ID NO:355 (SSYLH). In another embodiment, the thereof binds CB1 and comprises an amino acid sequence isolated antibody or fragment thereof comprises a light chain comprising one or more mutations in the Fc region. In a CDR2 sequence having at least 80%, at least 85%, at least further embodiment, the isolated antibody or antigen bind 90%, at least 95% at least 96%, at least 97%, at least 98%, ing fragment thereof has a mutation at position 228 and/or or at least 99% homology to the amino acid sequence of 330 and/or 331. In another embodiment, the isolated anti SEQ ID NO: 356 (STSNLAS). In another embodiment, the body or antigen binding fragment thereof has a mutation at US 2017/0210797 A1 Jul. 27, 2017 position 228 of the Fc region, wherein the Fc region is of the a corresponding non-humanized or chimeric antibody, IgG4 isotype. In a further embodiment, the mutation is wherein the humanized antibody or fragment and the cor S228P. In another embodiment, the isolated antibody or responding non-humanized or chimeric antibody comprise antigen binding fragment thereof has a mutation at position the same heavy and light chain CDRs. For example, in one 330 and/or position 331. In a further embodiment, the embodiment, the present invention provides a humanized isolated antibody or antigen binding fragment thereof has a antibody or fragment thereof comprising heavy chain mutation at position 330 and/or 331, wherein the Fc region CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and is of the IgG2 isotype. In a further embodiment, the isolated CDR3 according to SEQID NOs: 352, 353, 354, 355, 356, antibody or antigen binding fragment thereof has the fol and 357, respectively, wherein the humanized antibody lowing mutations in the Fc region: A330S and P331S. In exhibits greater binding affinity for CB1 receptor and/or another embodiment, the isolated antibody or antigen bind greater potency with respect to inhibition of CB1 receptor ing fragment thereof comprises an Fc region that is a hybrid agonist. In one embodiment, the humanized antibodies and Fc region. For example, in one embodiment, the Fc region fragments provided herein exhibit at least 50% greater, at is a hybrid IgG2/IgG4 Fc region, wherein the CH1 and hinge least 100% greater, at least 2 fold greater, at least 3 fold regions are derived from IgG2, and the CH2 and CH3 greater, at least 4 fold greater, at least 5 fold greater, or at regions are derived from IgG4. least 10 fold greater potency relative to the corresponding 0042. Thus, in one embodiment, the antibody or antigen non-humanized or chimeric antibody. In a further embodi binding fragment thereof provided herein is a chimeric or ment, the potency is measured by inhibition of CB1-cAMP humanized antibody or fragment containing heavy and light production. chain CDRs selected from the CDRs provided herein, or 0046 Potency of CB1 receptor antibodies provided conservative variants of the CDRs provided herein, wherein herein may be measured by any method known in the art. the isolated antibody or fragment thereof comprises an Fc For example, in one embodiment, potency of the antibodies region comprising modifications that alter antibody effector and fragments provided herein is measured by intracellular functions. For example, in one embodiment, the isolated cAMP levels or ERK phosphorylation. For example, antibody or antigen binding fragment thereof comprises potency may be measured by the level of inhibition cAMP light and heavy chain CDRs according to SEQ ID NOs: production in a cAMP functional assay (Cisbio) or inhibition 352-357, or conservative variants thereof, and further com of WIN55.212-induced ERK phosphorylation in a Western prises an IgG2-IgG4 hybrid Fc region, an IgG2 Fc region blot. comprising amino acid mutations at positions 330 and 331 0047. In some embodiments, the present invention pro (e.g., A330S and P331S), or an IgG4 Fc region comprising vides an antibody or antigen binding fragment thereof that is an amino acid mutation at position 228 (e.g., S228P). capable of competing with the antibody or antigen binding 0043. In one embodiment, the present invention provides fragments thereof disclosed herein for binding to CB1 an isolated antibody orantigenbinding fragment thereofthat receptor. In some other embodiments, the present invention binds to CB1, wherein the antibody or fragment has a provides an antibody or antigen binding fragment thereof binding affinity Kd for CB1 receptor of about 70 nM or less, that is capable of specifically binding to essentially the same about 60 nM or less, about 50 nM or less, about 40 nM or epitope on CB1 receptor as the antibodies or antigen binding less, about 30 nM or less, about 25 nM or less, about 20 nM fragments disclosed herein. Such antibodies can be identi or less, about 15 nM or less, about 10 nM or less, about 8 fied using routine competition binding assays. In certain nM or less, about 6 nM or less, about 5 nM or less, about 4 embodiments, competition is measured by ELISA, flow nM or less, about 3 nM or less, about 2 nM or less, or about cytometry, or Surface plasmon resonance (SPR) assay. 1 nM or less. In one embodiment, present invention provides 0048. In some embodiments, the antibodies and frag an isolated antibody or fragment thereof that binds to CB1, ments thereof are conjugated to one or more agents selected wherein the antibody or fragment has a binding affinity Kd from the group including an additional therapeutic agent, a for CB1 receptor in the range of about 1 nM to about 100 cytotoxic agent, an immunoadhesion molecule, and an imag nM, about 2 nM to about 75 nM, about 3 nM to about 50 nM, ing agent. In some embodiments, the imaging agent is about 4 nM to about 10 nM, or has a binding affinity Kd for selected from the group consisting of a radiolabel, an CB2 receptor that is about 50 nM, or about 40 nM, or about enzyme, a fluorescent label, a luminescent label, a biolumi 30 nM, or about 20 nM, or about 10 nM, or about 5 nM, or nescent label, a magnetic label, and biotin. about 4 nM, or about 3 nM or about 2 nM, or about 1 nM. 0049. In one aspect, methods are provided for modulating 0044. In one embodiment, the present invention provides the signaling activity of CB1 receptor comprising contacting an isolated antibody orantigenbinding fragment thereofthat a cell expressing CB1 receptor with the antibody or frag is at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, ment thereof disclosed herein. In some embodiments, the at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, methods provided result in inhibition of the activity of CB1 at least 10 fold, at least 11 fold, at least 12 fold, at least 13 receptor signaling. In some embodiments, the methods pro fold, at least 14 fold, or at least 15 fold more potent than the vided result in increased activity of CB1 receptor signaling. small molecule rimonabant, wherein the potency of the In some embodiments, the modulation of CB1 receptor antibody or fragment or rimonabant is measured by inhibi signaling activity is indirect, such as though an allosteric tion of CB1 receptor antagonist-mediated signal transduc modulator. In some embodiments, the modulation of CB1 tion in a cAMP assay. In a further embodiment, the isolated receptor signaling activity is biased for Galpha i?o mediated antibody or antigen binding fragment thereof is humanized. signaling versus beta arrestin mediated signaling. 0045. In one embodiment, the present invention provides 0050. In one aspect, methods for treating a disease or an isolated humanized antibody or antigen binding fragment disorder responsive to antagonism or agonism of CB1 thereof that binds to CB1, wherein the antibody or fragment receptor in a Subject in need thereof are provided. In some exhibits greater binding affinity and/or greater potency than embodiments, the methods comprise administering to the US 2017/0210797 A1 Jul. 27, 2017 Subject an anti-CB1 receptor antibody or antigen binding phage display library is derived from cells isolated from the fragment thereof as disclosed herein. In one embodiment, immunized mammals. In a further embodiment, the phage the Subject is a mammal. In a further embodiment, the display library is derived from naive human immunoglobu Subject is a human. In some embodiments, the disease or lin sequences. disorder is obesity, diabetes, dyslipidemia, metabolic dis eases, fibrosis, non-alcoholic steatohepatitis (NASH), liver BRIEF DESCRIPTION OF THE FIGURES disease, primary biliary cirrhosis, renal disease, kidney 0053 FIG. 1A is a set of histograms showing binding of fibrosis, chronic kidney disease, osteoporosis, atherosclero P2A12 Bril mAb (left column), PA2LR3-P2D3 (middle sis, cardiovascular disease, cancer, an inflammatory disease, column), or PA2R3-P1A7 (right column) at 300 nM (top pain, MS spasticity, and ocular diseases, including glau row) or 30 nM (bottom row) to Trex-CHO Native human coma. In some embodiments, the disease or disorder is, for CB1 cell line (native CB1 receptor expressing: dark gray example, obesity, diabetes, fibrosis, liver disease, cardiovas lines), Trex-CHO CB1 T210A/fusion partner (overex cular disease, or cancer, and the method provided results in pressed CB1; medium gray lines), or Trex-CHO parental inhibition of the activity of CB1 receptor. In some embodi cell line (no CB1 receptor expression; light gray lines). FIG. ments, the disease or disorder is, for example, pain or 1B is a set of histograms showing binding of PA2R3-P1F1 glaucoma, and the method provided results in activation or (left column), PA2LR3-P2E5 (middle column), or PA2LR3 increase of CB1 receptor activity. P3B10 (right column) at 300 nM (top row) or 30 nM (bottom 0051. In one aspect, a method for detecting CB1 receptor row) to Trex-CHO Native CB1 cell line (native human CB1 in a cell, tissue, or subject is provided, the method compris receptor expressing: dark gray lines), Trex-CHO CB1 ing contacting a cell with a CB1 receptor binding antibody T210A/fusion partner (overexpressed CB1; medium gray or antigen binding fragment provided herein. In one embodi lines), or Trex-CHO parental cell line (no CB1 receptor ment, the cell is present in a Subject. In another embodiment, expression; light gray lines). FIG. 1C is a set of histograms the cell is present in a human Subject. In another embodi showing binding of PA2LR3-P3B8 (left column) or ment, the CB1 receptor expression level on cells is corre PA2LR3-P1H4 (right column) at 300 nM (top row) or 30 nM lated with a disease state. Thus, in one aspect, the present (bottom row) to Trex-CHO Native human CB1 cell line invention provides methods of using antibodies and frag (native CB1 receptor expressing: dark gray lines), Trex ments thereof that specifically bind to CB1 receptor as tools CHO CB1 T210A/fusion partner (overexpressed CB1; for the diagnosis and/or prognosis of human diseases. In one medium gray lines), or Trex-CHO parental cell line (no CB1 embodiment, the present invention provides methods for receptor expression; light gray lines). FIG. 1D is a set of imaging CB1 receptor comprising the use of the CB1 histograms showing binding of PA2LR3-P4B1 (left col receptor antibodies and fragments disclosed herein. In one umn), PA2LR3-P4B5 (middle column), or PA2LR3-P4C6 embodiment, the method for detecting CB1 receptor is (right column) at 300 nM (top row) or 30 nM (bottom row) achieved with a CB1 receptor antibody or fragment thereof to Trex-CHO Native human CB1 cell line (native CB1 disclosed herein that selectively binds CB1 receptor. In a receptor expressing: dark gray lines), Trex-CHO CB1 further embodiment, the selective CB1 receptor antibody or T210A/fusion partner (overexpressed CB1; medium gray fragment thereof does not exhibit agonistic or antagonistic lines), or Trex-CHO parental cell line (no CB1 receptor activity. In a further embodiment, the selective CB1 receptor expression; light gray lines). FIG. 1E is a set of histograms antibody or fragment thereof does not internalize. In one showing binding of PA2LR3-P4G10 (left column) or embodiment, the present invention provides diagnostic and PA2LR3-P6D7 (right column) at 300 nM (top row) or 30 nM imaging methods comprising the use of a CB1 receptor (bottom row) to Trex-CHO Native human CB1 cell line antibody or fragment that is conjugated to an imaging agent (native CB1 receptor expressing: dark gray lines), Trex Such as, for example, a radiolabel, an enzyme, a fluorescent CHO CB1 T210A/fusion partner (overexpressed CB1; label, a luminescent label, a bioluminescent label, a mag medium gray lines), or Trex-CHO parental cell line (no CB1 netic label, or biotin. receptor expression; light gray lines). FIG. 1F is a set of 0052. In one embodiment, the invention provides a host histograms showing binding of PA2LR3-P1G6 (left col cell expressing an isolated antibody or fragment thereof that umn), PA2LR3-P1H4 (middle column), or PA2LR3-P2B8 specifically binds to CB1 receptor. In another embodiment, (right column) to Trex-CHO parental cell line (no CB1 a method for making an antibody or fragment thereof that receptor expression; top row), Trex-CHO CB1 T210A/ specifically binds to CB1 receptor is provided, the method fusion partner cell line (overexpressed CB1; middle row), or comprising immunizing mammals with purified CB1 recep Trex-CHO A156 cell line (native human CB1 receptor tor or an antigenic fragment thereof, CB1/lipid complexes, expressing; bottom row). CB1 receptor iCAPS, and/or CB1 receptor DNA. In a 0054 FIG. 2 shows the selectivity of two of the CB1 further embodiment, the immunized mammals are mice. In receptor antibodies, PA13R3-P1C4 and 36E12B6C2, for another embodiment, the mammals are immunized one, two, binding to cells expressing CB1. FIG. 2A (showing three, four, five, or more times with purified CB1 or an PA13R3-P1C4 binding) and FIG. 2B (showing 36E12B6C2 antigenic fragment thereof, CB1/lipid complex, CB1 recep binding) show that both antibodies bound to A156 (native tor iCAPS, and/or CB1 receptor DNA prior to harvesting human CB1 receptor expressing) and, to an even greater cells from the immunized mammals. In a further embodi extent, A56 (over-expresses CB1 receptor modified by ment, the antibody or fragment thereof that specifically T210A mutation and ICL3 replacement with fusion partner binds to CB1 receptor is generated from a hybridoma cell fusion partner) but did not exhibit binding to non-CB1 line comprising cells derived from the immunized mam receptor expressing CHO cells, CB2 expression cell line, or mals. In another embodiment, the antibody or fragment 5HT2b expression cell line. Expression of CB2 (FIG. 2C) thereof that specifically binds to CB1 receptor is generated and 5HT2b (FIG. 2D) was confirmed in CB2 expression and from a phage display library. In a further embodiment, the 5HT2b expression cell lines, respectively. US 2017/0210797 A1 Jul. 27, 2017 0055 FIG. 3 shows the results of a competition assay to nalization. The top row of histograms in FIG. 9A shows determine if 36E12B6C2 and P1C4 bind to similar epitopes. surface expression of CB1 following treatment with WIN55, Trex CHO A156 native human CB1 cells were incubated 212 or control, or pre-treatment with CB1 specific neutral with competitor IgGs (PA13R3-P1C4 IgG or Fab and antagonist AM6545 followed by WIN55.212. The middle 36E12B6C2) followed by different concentrations of stain and bottom rows of histograms in FIG. 9A show surface ing IgGs (300 nM or 75 nM of P1C4, FIG.3A: 80 nM or 25 expression of CB1 following pre-treatment with CB1 anti nM of 36E12B6C2, FIG. 3B). bodies PA2LR3-P3A8, PA2LR3-P3F8, PA2LR3-P5B11, 0056 FIG. 4 shows the results of the cAMP functional PA2LR3-P5E7, PA2LR3-P6B12, PA2LR3-P6G7, PA3R3 antagonist assay. Antibodies 36E12B2H8 (FIG. 4A) and P4D5, PA2LR3-P4B1, PA2LR3-P4B5, PA2LR3-P4C6, and PA13R3-P1C4 (FIG. 4B) exhibited antagonistic activity that PA2LR3-P4G10, or negative control P2A12 followed by was equipotent (36E12B2H8) or more potent (PA13R3 treatment with WIN55,212. FIG. 9B shows that CB1 anti P1C4) relative to positive control small molecule CB1 bodies alone do not induce CB1 receptor internalization. The receptor inhibitors AM251 (FIG. 4C), SR141716A (rimona top row of histograms in FIG. 9B show surface expression bant) (FIG. 4D), and AM6545 (FIG. 4E). P2A12 and of CB1 following treatment with WIN55.212 or control, or hybridoma IgG isotype were used as negative controls pre-treatment with CB1 specific neutral antagonist AM6545 (FIGS. 4F and 4G). followed by WIN55.212. The middle and bottom rows of 0057 FIG. 5A is a set of Western blots showing phos histograms in FIG. 9B show surface expression of CB1 phorylated ERK (pERK) and total ERK in Trex-CHO native following treatment with CB1 antibodies PA2LR3-P3A8, human CB1 receptor cells following CB1 receptor expres PA2LR3-P3F8, PA2LR3-P5B11, PA2LR3-P5E7, PA2LR3 sion and treatment with control IgG, positive control Small P6B12, PA2LR3-P6G7, PA3R3-P4D5, PA2LR3-P4B1, molecule AM6545, or phage derived mAb PA13R3-P1C4 or PA2LR3-P4B5, PA2LR3-P4C6, and PA2LR3-P4G10, or PA13R3-P1 E4, followed by treatment with 100 nm of CB1 negative control P2A12 receptor agonist WIN55.212. The Western blots shown are 0062 FIG. 10 shows the results of the cAMP functional from 10 minutes following WIN55.212 activation (left pan antagonist assay for humanized versus chimeric P1C4 anti els) or 15 minutes following WIN55.212 activation (right bodies. Humanized antibody P1C4-HO exhibited antagonis panels). FIG. 5B is a set of Western blots showing pERK and tic activity that was similar to the chimeric P1C4 antibody. total ERK in Trex-CHO native human CB1 receptor cells Humanized antibodies P1C4-H4 and P1C4-H2 exhibited following CB1 receptor expression and treatment with con antagonistic activity that was more potent relative to the trol IgG1, control IgG2, WIN55.212, AM6545, or chimeric P1C4 antibody or to positive control small mol hybridoma-derived mAb 36E12B2E5, 36E12B6C2, or ecule CB1 receptor inhibitor rimonabant. 36E12B2F2, followed by WIN55.212 activation. 0063 FIG. 11 shows the binding affinity, cross-reactivity, 0058 FIG. 6A shows the results of the cAMP functional and specificity of humanized P1C4 antibodies as measured assay performed in the absence of CP55940 to assess by flow cytometry. Humanized P1C4 antibodies P1C4-H2 potential agonist activity of PA2LR3-P2D3, PA2LR3-P4B1, and P1C4-H4 exhibited superior binding affinity to both PA2LR3-P6B12, and PA2LR3-P6G6, relative to controls native human CB1 cells (FIG. 11A, top panel) and to depicted in FIG. 6B: CP55940 (positive control), P2A12 overexpressed CB1 cells (FIG. 11A, bottom panel) relative (negative control), or PA2R3-P1A7 (negative control). FIG. to the P1C4 chimeric antibody. None of the chimeric or 6C shows the results of the cAMP functional assay per humanized antibodies bound to mouse cells expression formed in the presence of CP55940 to assess potential mouse CB1, TRex-CHO parental cells, or TRex-CHO cells allosteric modulator activity of PA2LR3-P2D3, PA2LR3 expressing human CB2 (FIG. 11B). P4B1, PA2LR3-P6B12, and PA2LR3-P6G6, relative to con 0064 FIG. 12 shows the affinity of unlabeled P4B5 trols depicted in FIG. 6D: CP55940 alone (positive control), antibody versus Vivotag 680 XL-labeled P4B5 antibody to P2A12 (negative control), or PA2R3-P1A7 (negative con CB1 on cells. trol). 0065 FIG. 13 A shows the detection of labeled P4B5 0059 FIG. 7 shows the results of a cAMP assay con antibody in the heart, lungs, liver, kidneys, stomach, intes ducted to assess the inverse agonist or neutral antagonist tines, and bladder at time points Oh, 1 h, 5h, 24h, 48 h, 72 activity of PA13R3-P1C4 and 36E12B6C2. AM6545 and h, 96 h, and 144 h (13A.1); and the detection of labeled SR141716A were used as positive controls for neutral P4B5 antibody in the brain at timepoints Oh, 1 h, 5h, 24 h. antagonist and inverse agonist respectively. 48 h, 72 h, 96 h, and 144 h (13A2). FIG. 13B shows the 0060 FIG. 8A shows an iCAPS ELISA binding assay detection of labeled antibody in the brain including both assessing 36E12B6C2 Fab (top left panel) or IgG (top right tissue and blood (left panel) versus detection of labeled panel), or P1 F7Fab (bottom left panel) or Fab (bottom right antibody in the brain with the blood signal subtracted (i.e., panel) to rBril-0918, empty iCAPS, iCAPS that do not brain tissue only; right panel). express CB1 receptor (h13h iCAPS), or iCAPS that express 0066 FIG. 14 shows the SEC profiles and SDS-PAGE human CB1 receptor (A138 iCAPS and A139 iCAPS). FIG. analyses for PA13R3-P1C4 humanized variants expressed in 8B shows an iCAPS ELISA binding assay assessing 293 and CHO-K cells. FIG. 14A shows the SEC profile (top) PA13R3-P1C4 Fab (top left panel) or IgG (top right panel), and SDS-PAGE (bottom) analyses for one of the 293 Free or P1F7 Fab (bottom left panel) or Fab (bottom right panel) Style batches. FIG. 14B shows the SEC profile (top) and to rBril-0918, empty iCAPS, iCAPS that do not express CB1 SDS-PAGE (bottom) analyses for one of the CHO-K1 receptor (h13h iCAPS), or iCAPS that express human CB1 batches. receptor (A138 iCAPS and A139 iCAPS). 0067 FIG. 15 shows cAMP functional assays for 0061 FIGS. 9A and 9B show CB1 receptor internaliza PA13R3-P1C4 humanized variants compared with parental tion following various treatments. FIG. 9A shows that CB1 chimeric PA13R3-P1C4 and P2A12 mAb, a non-GPCR antibodies do not block WIN55.212 induced receptor inter targeting mAb negative control antibody of IgG1 isotype. US 2017/0210797 A1 Jul. 27, 2017 0068 FIG. 16 shows a comparison of the activity of I0081 FIG. 29 shows RT-PCR expression data measuring humanized variants P1C4-h2-IgG2 and P1C4-h2-IgG4 with TGFB expression levels in primary hepatic stellate cells rimonabant, AM6545 and the P2A12-IgG1 negative control treated with the indicated antibodies, concentrations, and antibody in 1.5 M forskolin stimulated TRex-CHO CB1 controls. cells (FIG. 16A) as well as 5 uM forskolin stimulated I0082 FIG. 30 shows RT-PCR expression data measuring TRex-CHO CB1 cells (FIG. 16B). TIMP1 expression levels in primary hepatic stellate cells 0069 FIG. 17 shows the effect of increasing P1C4-h2 treated with the indicated antibodies, concentrations, and IgG4 concentrations on CP55,940 (FIG. 17A and WIN55, controls. 212 (FIG. 17C). Schild plots for each treatment are also I0083 FIG. 31 shows RT-PCR expression data measuring shown (FIGS. 17B and 17D). C-SMA expression levels in primary hepatic stellate cells 0070 FIGS. 18A and 18B show Western blot ERK acti treated with the indicated antibodies, concentrations, and vation assays measuring the ability of PA13R3-P1C4 controls. humanized variants to block WIN55,212 mediated ERK activation. DETAILED DESCRIPTION (0071 FIG. 19A shows a flow-cytometry based CB1 I0084. In one aspect, the present invention provides anti receptor internalization study under various induction con gen binding proteins such as antibodies and antigen-binding ditions, in the absence of inhibitor (Panel A), or the presence fragments thereof that bind selectively to human cannabi of rimonabant (Panel B) or PA13R3-P1C4 humanized vari noid 1 (CB1) receptor. The antibodies and fragments thereof ants (Panels C–G). FIG. 19B shows the same CB1 receptor are functional antibodies that agonize or antagonize CB1 internalization assay investigating the effect of P1C4-h2 receptor, or are selectively recognizing CB1 withoutagonist cloned into the different human Fc frameworks IgG2 and or antagonist activity. IgG4. I0085. As used herein, the term “antibody” refers to 0072 FIG. 20, A-D show flow cytometry data measuring binding proteins having at least one antigen-binding domain binding of humanized PA13R3-P1C4 antibody variants to and includes monoclonal antibodies fragments and/or vari TRex-CHO cells stably transfected with tetracycline induc ants thereof including recombinant polypeptides, fusion ible human CB1. FIG. 20, E-M show binding selectivity and proteins, and immunoconjugates. Thus, the terms “anti cross-reactivity of humanized PA13R3-P1C4 variants to body,” “antibody fragment, and “antibody variant” are used human CB1 versus human CB2 and mouse CB1. interchangeably herein. Examples of antibody fragments of 0073 FIG. 21 shows flow cytometry data measuring the the invention include, but are not limited to, the Fab frag binding of antibodies (indicated at top) to cells expressing ment, consisting of VL, VH, CL and CHI domains; the Fc various CB1 constructs (indicated at left). fragment, consisting of the VH and CHI domains; the Fv 0074 FIG.22 shows antibody mediated cytotoxicity and fragment consisting of the VL and VH; the dAb fragment complement dependent cytotoxicity of humanized P1C4 consisting of a VH domain; isolated CDR regions: F(ab'), a variants P1C4-h2-IgG2 and P1C4-h2-IgG4 in Daudi cells. bivalent fragment comprising two linked Fab fragments; and FIGS. 22A-C show the effect of P14C variants in antibody single chain Fv molecules (sclv). The CB1 receptor binding mediated toxicity assays. FIG.22D shows the effect of P14C antibodies provided herein may be generated from any variants in complement dependent cytotoxicity assays. species including, but not limited to, mouse, rat, rabbit, 0075 FIG. 23 shows Western Blot analysis assessing primate, llama and human. The CB1 receptor binding anti recognition of denatured CB1 protein by the indicated P1C4 bodies may be chimeric, humanized, or fully human anti primary antibodies or control antibodies, and anti-human bodies. (FIG. 23A) or anti-mouse (FIG. 23B) secondary antibodies. 0086. As used herein, the term "derived' when used to Purified human IgG with human secondary (FIG.23A, Lane refer to a molecule or polypeptide relative to a reference 1), and mouse primary with anti-rabbit secondary (FIG. antibody or other binding protein, means a molecule or 23B, Lane 11) are presented as negative controls. polypeptide that is capable of binding with specificity to the same epitope as the reference antibody or other binding 0076 FIG. 24 shows the results of flow cytometry bind protein. ing experiments (FIG. 24A), and inhibition of cAMP pro duction (FIG. 24B), by chimeric and humanized P1C4 Fab I0087. The use of the singular includes the plural unless antibody fragments incubated with cells expressing CB1 specifically stated otherwise. The word “a” or “an” means receptor. “at least one' unless specifically stated otherwise. The use of “or means “and/or unless stated otherwise. The meaning 0077 FIG. 25 shows positive CB1-specific staining in of the phrase “at least one' is equivalent to the meaning of macrophage, hepatocytes, and hepatic myofibroblasts in the phrase “one or more.” Furthermore, the use of the term early NASH (left panel), NASH fibrosis (middle panel) and “including, as well as other forms, such as “includes and late fibrosis (right panel) samples. “included,” is not limiting. Also, terms such as “element” or 0078 FIG. 26 shows that no staining was observed with “component' encompass both elements or components com isotype controlled irrelevantantibodies in cells derived from prising one unit and elements or components comprising either normal (middle panel) or NASH fibrosis (right panel) more than one unit unless specifically stated otherwise. cells. I0088. The antibodies and antigen-binding fragments 0079 FIG. 27 shows no CB1 specific staining in normal thereof disclosed herein are specific for cannabinoid 1 (CB1) tissues. receptor. By “specific for is meant that the antibodies and 0080 FIG. 28 shows RT-PCR expression data measuring fragments thereof bind CB1 receptor with greater affinity Pro-collagen A1 (I), in primary hepatic stellate cells treated (i.e., a lower binding affinity Kd value) than any other target. with PBS, non-functional control antibody, and P1C4-h2 Thus, antibodies and fragments thereofthat are selective for antibodies. CB1 receptor bind CB1 receptor with greater affinity (i.e., a US 2017/0210797 A1 Jul. 27, 2017 lower binding affinity Kd value) than any other cannabinoid to provide the optimum therapeutic response. An effective receptor or any other GPCR or any other target. The anti amount is also one in which any toxic or detrimental effects bodies and fragments or variants thereof may have a binding (i.e., side effects) of an antibody or antigen binding fragment affinity Kd value for CB1 receptor in the range of about 0.01 thereof are minimized or outweighed by the beneficial nM to about 500 nM, about 0.02 nM to about 250 nM, about effects. 0.02 to about 200 nM, about 0.05 to about 100 nM, about 0094. I. Modified Anti-CB1 Antibodies 0.05 to about 50 nM. The antibodies and fragments thereof 0095. In certain embodiments, anti-CB1 receptor anti may have a binding affinity Kd value for CB1 receptor of bodies disclosed herein may comprise one or more modifi about 500 nM, about 250 nM, about 200 nM, about 150 nM, cations. Modified forms of anti-CB1 receptor antibodies about 100 nM, about 75 nM, about 50 nM, about 25 nM, disclosed herein can be made using any techniques known in about 10 nM, about 5 nM, about 1 nM, about 500 pM, about the art. 250 pM, about 100 pM, about 50 pM, or about 10 pM. The 0096. In some embodiments, the anti-CB1 receptor anti antibodies and fragments thereof may have a binding affinity bodies and fragments thereof are conjugates further com Kd value for CB1 receptor of about 100 nM or less, about prising an agent selected from the group including an 75 nM or less, about 50 nM or less, about 10 nM or less, additional therapeutic agent, a cytotoxic agent, an immuno about 1 nM or less, about 500 pM or less, or about 100 pM adhesion molecule, and an imaging agent. In some embodi or less. ments, the imaging agent is selected from the group con 0089. As used herein, the term "agonist” refers to a sisting of a radiolabel, an enzyme, a fluorescent label, a compound that enhances the signaling activity of another luminescent label, a bioluminescent label, a magnetic label, compound or receptor site. and biotin. In some embodiments, the imaging agent is a 0090. As used herein, the term “antagonist” refers to a radiolabel selected from the group consisting of H, C, compound that inhibits, diminishes or prevents the signaling 35S, 6.Cu, 897r, 90Y. 99Tc, Ill In, 125I, 13 II, 177Lu, 166Ho, and activity of another compound at a receptor site and more 'Sm. In some embodiments, the therapeutic agent or generally refer to a compound that diminishes or prevents cytotoxic agent is selected from the group including an the activation and/or the signaling activity of a receptor. immunosuppressive agent, an immuno-stimulatory agent, an 0091 An “allosteric modulator is a compound that indi anti-metabolite, an alkylating agent, an antibiotic, a growth rectly modulates the agonistic effects of another compound. factor, a cytokine, an anti-angiogenic agent, an anti-mitotic For example, an allosteric modulator may indirectly modu agent, an anthracycline, a toxin, and an apoptotic agent. late the agonistic effect of a receptor agonist by inducing a I0097. In one embodiment, the isolated anti-CB1 receptor conformational change within the protein structure. Allos antibody or antigen binding fragment disclosed herein is teric modulators may be positive (amplify the agonistic conjugated to a CB1 antagonist. Non-limiting examples of effect of the agonist compound) or negative (diminish the known CB1 antagonists include rimonabant, taranabant, effect of the agonist compound) modulators. VD60, Isis-414930 Antisense CB1, JD5037, AM6545, and 0092. As used herein, the terms “treatment” or “treating TM38837. In one embodiment, the isolated anti-CB1 recep refers to both therapeutic treatment and prophylactic or tor antibody or antigen binding fragment disclosed herein is preventive measures. A subject in need of treatment is a conjugated to rimonabant. In one embodiment, the isolated subject that already has the disease or disorder as well as antibody or antigen binding fragment thereof that is conju those that may develop the disease or disorder and in whom gated to the cytotoxic agent is a CB1 receptor agonist. In the object is to prevent, delay, or diminish the disease or another embodiment, the isolated antibody or antigen bind disorder. The methods of “treatment disclosed herein ing fragment that is conjugated to the cytotoxic agent is a employ administration to a Subject, an antibody or antigen CB1 receptor neutral binder that allows receptor internal binding fragment disclosed herein, for example, a subject ization to occur. having a CB1-associated disease or disorder (e.g., a fibrotic 0098. In another aspect, the isolated anti-CB1 receptor disease) or predisposed to having Such a disease or disorder, antibody or antigen binding fragment disclosed herein is in order to prevent, cure, delay, reduce the severity of, or conjugated to a chemotherapeutic agent. A “chemotherapeu ameliorate one or more symptoms of the disease or disorder tic agent' is a chemical compound useful in the treatment of or recurring disease or disorder, or in order to prolong the cancer. Examples of chemotherapeutic agents include alky survival of a subject beyond that expected in the absence of lating agents such as thiotepa and CYTOXANR) cyclospho such treatment. As used herein, the term “subject' denotes a sphamide; alkyl Sulfonates Such as buSulfan, improSulfan mammal. Such as a rodent, a feline, a canine, and a primate. and piposulfan; aziridines such as benzodopa, carboquone, Preferably a subject according to the invention is a human. meturedopa, and uredopa; ethylenimines and methylam 0093. A “therapeutically effective amount,” as used elamines including altretamine, triethylenemelamine, trieth herein, refers to the amount of a compound or composition ylenephosphoramide, triethylenethiophosphoramide and that is necessary to provide a therapeutic and/or preventative trimethylolomelamine; acetogenins (especially bullatacin benefit to the subject. Atherapeutically effective amount will and bullatacinone); a camptothecin (including the synthetic vary depending upon the Subject and disease condition being analogue topotecan); bryostatin: cally statin, CC-1065 (in treated, the weight and age of the subject, the severity of the cluding its adoZelesin, carZelesin and bizelesin Synthetic disease condition, the manner of administration and the like, analogues); cryptophycins (particularly cryptophycin 1 and which can readily be determined by one of ordinary skill in cryptophycin 8); dolastatin; duocarmycin (including the the art. The dosages for administration can range from, for synthetic analogues, KW-2189 and CB1-TM1); eleuther example, about 1 ng to about 10,000 mg, about 1 ug to about obin: pancratistatin; a sarcodictyin; spongistatin: nitrogen 5,000 mg, about 1 mg to about 1,000 mg, about 10 mg to mustards such as chlorambucil, chlornaphazine, cholophos about 100 mg. of an antibody or antigen binding fragment phamide, estramustine, ifosfamide, mechlorethamine, thereof, disclosed herein. Dosage regiments may be adjusted mechlorethamine oxide hydrochloride, melphalan, novem US 2017/0210797 A1 Jul. 27, 2017 bichin, phenesterine, prednimustine, trofosfamide, uracil pounds such as (S)- N-6-benzo1.3dioxol-5-yl-1-(5-(4- mustard; nitroSureas such as carmustine, chlorozotocin, fluoro-benzoyl)-pyridin-3-ylmethyl)-2-oxo-1,2-dihydro fotemustine, lomustine, nimustine, and ranimustine; antibi pyridin-3-yl)-2-methylamino-propionamide, XIAP otics such as the enediyne antibiotics (e.g., calicheamicin, antisense), HDAC inhibitors (HDACI) and kinase inhibitors especially calicheamicin gamma 11 and calicheamicin (Sorafenib). In one embodiment, the isolated antibody or omega 11 (see, e.g., Agnew, Chem Intl. Ed. Engl., 33: antigen binding fragment that is conjugated to the cytotoxic 183-186 (1994)); dynemicin, including dynemicin A; bis agent is a CB1 receptor agonist. phosphonates, such as clodronate; an esperamicin; as well as 0099. In some embodiments, the binding protein is con neocarzinostatin chromophore and related chromoprotein jugated directly to the agent. In other embodiments, the enediyne antibiotic chromophores), aclacinomysins, actino binding protein is conjugated to the agent via a linker. mycin, authramycin, azaserine, bleomycins, cactinomycin, Suitable linkers include, but are not limited to, amino acid carabicin, carminomycin, carzinophilin, chromomycinis, and polypeptide linkers disclosed herein. Linkers may be dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- cleavable or non-cleavable. norleucine, ADRIAMYCINR) doxorubicin (including mor 0100. In certain embodiments, the antibodies and frag pholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyr ments thereof are bispecific or bi-functional antibodies. The rolino-doxorubicin and deoxydoxorubicin), epirubicin, term “bispecific antibodies' refers to molecules which com esorubicin, idarubicin, marcellomycin, mitomycins such as bine the antigen-binding sites of two antibodies within a mitomycin C, mycophenolic acid, nogalamycin, olivomy single molecule. Thus, a bispecific antibody is able to bind cins, peplomycin, potfiromycin, puromycin, quelamycin, two different antigens simultaneously. A bispecific antibody rodorubicin, Streptonigrin, Streptozocin, tubercidin, uben typically is an artificial hybrid antibody having two different imex, Zinostatin, Zorubicin; anti-metabolites such as metho heavy chain/light chain pairs and two different binding sites trexate and 5-fluorouracil (5-FU); folic acid analogues such or epitopes. Bispecific antibodies can be monoclonal, pref as denopterin, methotrexate, pteropterin, trimetrexate; erably human or humanized, antibodies that have binding purine analogs such as fludarabine, 6-mercaptopurine, thia specificities for at least two different antigens. miprine, thioguanine; pyrimidine analogs such as ancit 0101. In one embodiment, the bispecific antibody and/or abine, azacitidine, 6-azauridine, carmofur, cytarabine, dide fragment thereof has binding specificities directed towards oxyuridine, doxifluridine, enocitabine, floxuridine: CB1 and a second target antigen. In certain embodiments, androgens Such as calusterone, dromoStanolone propionate, the bispecific antibody and/or fragment thereof has binding epitiostanol, mepitiostane, testolactone; anti-adrenals such specificities directed toward CB1 and TGF-B, 2-AG, PDGF as aminoglutethimide, mitotane, triloStane; folic acid replen B, IL-6, anandamide (AEA), or LOXL-2. isher Such as frolinic acid; aceglatone; aldophosphamide 0102 The antibodies and fragments disclosed herein may glycoside; aminolevulinic acid; eniluracil; amsacrine; bind to one or more target antigens selected from the group bestrabucil; bisantrene; ediatraxate; defofamine; demecol consisting of carbonic anhydrase IX, alpha-fetoprotein, cine; diaziquone; elfornithine; elliptinium acetate; an epoth C.-actinin-4, A3, antigen specific for A33 antibody, ART-4, ilone; etoglucid, gallium nitrate; hydroxyurea; lentinan; B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP lonidainine; maytansinoids such as maytansine and ansami 1, CASP-8/m, CCCL19, CCCL21, CD1, CD1a, CD2, CD3, tocins; mitoguaZone; mitoxantrone; mopidanmol; nitraerine; CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18. pentostatin: phenamet, pirarubicin; losoxantrone; podoph CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, yllinic acid; 2-ethylhydrazide; procarbazine; PSKR) poly CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, saccharide complex (JHS Natural Products, Eugene, Oreg.); CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, razoxane, rhizoxin; sizofiran; Spirogermanium; tenuaZonic CD74, CD79a, CD80, CD83, CD95, CD126, CD132, acid; triaziquone: 2,2'22"-trichlorotriethylamine; trichoth CD133, CD138, CD147, CD154, CDC27, CDK-4/m, ecenes (especially T-2 toxin, Verracurin A, roridin A and CDKN2A, CXCR4, colon-specific antigen-p (CSA.p), CEA anguidine); urethan; vindesine; dacarbazine; mannomustine; (CEACAM5), CEACAM1, CEACAM6, c-met, DAM, mitobronitol; mitolactol; pipobroman, gacytosine; arabino EGFR, EGFRVIII, EGP-1, EGP-2, ELF2-M, Ep-CAM, Flt side ("Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., 1, Flt-3, folate receptor, G250 antigen, GAGE, gp100, TAXOL(R) paclitaxel (Bristol-Myers Squibb Oncology, GROB. HLA-DR, HM1.24, human chorionic gonadotropin Princeton, N.J.), ABRAXANETM Cremophor-free, albumin (HCG) and its subunits, HER2/neu, HMGB-1, hypoxia engineered nanoparticle formulation of paclitaxel (Ameri inducible factor (HIF-1), HSP70-2M, HST-2, Ia, IGF-1R, can Pharmaceutical Partners, Schaumberg, Ill.), and TAXO IFN-y, IFN-C, IFN-?3, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, TERE(R) doxetaxel (Rhone-Poulenc Rorer, Antony, France); IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, chloranbucil; GEMZAR(R) gemcitabine; 6-thioguanine; mer IL-23, IL-25, insulin-like growth factor-1 (IGF-1), KC4 captopurine; methotrexate; platinum analogs such as cispla antigen, KS-1-antigen, KS1-4, Le-Y. LDR/FUT. macro tin and carboplatin: vinblastine; platinum: etoposide (VP phage migration inhibitory factor (MIF), MAGE, MAGE-3, 16); ifosfamide; mitoxantrone; Vincristine; NAVELEBINE(R) MART-1, MART-2, NY-ESO-1, TRAG-3, mCRP, MCP-1, Vinorelbine; novantrone; teniposide; ediatrexate; daunomy MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, cin; aminopterin: Xeloda; ibandronate; CPT-11: topoi MUC5, MUM-1/2, MUM-3, NCA66, NCA95, NCA90, somerase inhibitor RFS 2000; difluorometlhylornithine antigen specific for PAM-4 antibody, placental growth fac (DMFO); retinoids such as retinoic acid; capecitabine; and tor, p53, PLAGL2, prostatic acid phosphatase, PSA, pharmaceutically acceptable salts, acids or derivatives of PRAME, PSMA, PIGF, IGF, IGF-1R, IL-6, RS5, RANTES, any of the above. Also included in the definition are pro T101, SAGE, S100, survivin, survivin-2B, TAC, TAG-72, teasome inhibitors such as bortezomib (Velcade), BCL-2 tenascin, TRAIL receptors, TNF-C. Tn antigen, Thomson inhibitors, IAP antagonists (e.g. Smac mimics/XIAP and Friedenreich antigens, tumor necrosis antigens, VEGFR, cIAP inhibitors such as certain peptides, pyridine com ED-B fibroncotin, WT-1, 17-1A-antigen, complement fac US 2017/0210797 A1 Jul. 27, 2017 tors C3, C3a, C3b, C5a, C5, an angiogenesis marker, bcl-2. further immunization with CB1 receptor DNA and/or puri bcl-6, Kras, cMET, an oncogene marker and an oncogene fied CB1 receptor protein, membranes comprising CB1 product (see, e.g., Sensi et al., Clin Cancer Res 2006, receptor protein, or CB1 receptor iCAPS. In some embodi 12:5023-32; Parmiani et al., JImmunol 2007, 178:1975-79; ments, cells from immunized mice are used to generate Novellino et al. Cancer Immunol Immunother 2005, 54:187 hybridoma and phage libraries. 207). 0107. In some embodiments, CB1 receptor antibodies are 0103 Methods for making bispecific antibodies are well generated by recovering B cells from immunized mice and known. Traditionally, the recombinant production of bispe generating CB1 receptor antibody-producing hybridoma cific antibodies is based on the co-expression of two immu cells. The generation of hybridomas is a technique well noglobulin heavy chain/light chain pairs, where the two known in the art and involves fusion of antibody-producing heavy chains have different specificities (Milstein et al., cells with myeloma or other immortalized cells to generate Nature 305:537 (1983)). Because of the random assortment the immortalized antibody-producing hybridoma cell line of immunoglobulin heavy and light chains, the hybridomas (see, for example, Kohler and Milstein, 1975, Nature, 256: (quadromas) produce a potential mixture of ten different 495). Monoclonal antibodies produced by the hybridoma antibody molecules, of which only one has the correct cells can be isolated from the Supernatant by conventional bispecific structure. The purification of the correct molecule means of immunoglobulin purification Such as precipitation, is usually accomplished by affinity chromatography steps. chromatography, ultrafiltration, centrifugation, gel electro Similar procedures are disclosed in WO 93/08829 and in phoresis, and/or any other method known in the art. Super Traunecker et al., EMBO J 10:3655 (1991). Other methods natants or isolated monoclonal antibodies may be tested for for making bispecific antibodies are provided in, for binding to CB1 receptor by assessing binding to CB1 example, Kufer et al., Trends Biotech 22:238-244, 2004. receptor membranes relative to naive membranes. For 0104 Antibody variable domains with the desired bind example, Supernatants or isolated monoclonal antibodies ing specificities can be fused to immunoglobulin constant may be tested for binding to CB1 receptor in an ELISA. domain sequences. The fusion preferably is with an immu 0108. Another aspect of the invention provides methods noglobulin heavy chain constant domain, comprising at least of producing the antibodies and fragments or variants part of the hinge, C, and C regions. It may have the first described herein comprising the use of a phage library. heavy chain constant region (C) containing the site nec Methods for recombinantly generating antibodies via phage essary for light chain binding present in at least one of the display technology are known in the art (see, for example, fusions. DNAS encoding the immunoglobulin heavy chain Winter et al., Annu. Rev. Immunol. 12:433-455 (1994), fusions and, if desired, the immunoglobulin light chain, are McCafferty et al., Nature 348: 552-553 (1990), and Clack inserted into separate expression vectors, and are co-trans son et al. Nature 352:624 (1991)). In some embodiments, formed into a suitable host organism. For further details of spleens from immunized mice are used to isolate an array of generating bispecific antibodies see, for example Suresh et anti-CB1 receptor antibodies and form a random combina al., Meth Enzym 121:210 (1986). A variety of recombinant torial library of variable genes derived from those antibod methods have been developed for efficient production of ies. In some embodiments, rather than utilizing the cells bispecific antibodies, both as antibody fragments (Carter et from immunized mice to generate the phage display library, al. (1995), J. Hematotherapy 4: 463-470; Pluckthun et al. the library is generated from variable heavy and light chain (1997) Immunotechology 3: 83-105: Todorovska et al. genes of human primary blood lymphocytes. (2001) J. Immunol. Methods 248: 47-66) and full length IgG 0109. In some embodiments, the phage library is panned formats (Carter (2001) J. Immunol. Methods 248: 7-15). for CB1 receptor binding phage in at least 3 rounds of 0105. Unless otherwise stated, the practice of the present panning, and phage binders are Subsequently screened for invention employs conventional molecular biology, cell specific binding to CB1 receptor by ELISA. Specific binders biology, biochemistry, and immunology techniques that are may then be selected and converted into full antibodies. well known in the art and described, for example, in Meth 0110. In some embodiments, the antibodies and frag ods in Molecular Biology, Humana Press: Molecular Clon ments provided herein are chimeric antibodies or humanized ing: A Laboratory Manual, second edition (Sambrook et al., antibodies. Methods for generating chimeric and humanized 1989), Current Protocols in Immunology (J. E. Coligan et antibodies are well known in the art and summarized, for al., eds., 1991); Immunobiology (C. A. Janeway and P. example, in Lo, Benny, K. C., editor, in Antibody Engineer Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a ing. Methods and Protocols, volume 248, Humana Press, practical approach (D. Catty... ed., IRL Press, 1988-1989); New Jersey, 2004. Monoclonal antibodies: a practical approach (P. Shepherd 0111. A “chimeric antibody' is an antibody having at and C. Dean, eds., Oxford University Press, 2000); Phage least a portion of the heavy chain variable region and at least display: a laboratory manual (C. Barbas III et al., Cold Spring a portion of the light chain variable region derived from one Harbor Laboratory Press, 2001); and Using antibodies: a species; and at least a portion of a constant region derived laboratory manual (E. Harlow and D. Lane (Cold Spring from another species. For example, in one embodiment, a Harbor Laboratory Press, 1999). chimeric antibody may comprise murine variable regions 0106. In one aspect, the invention provides methods for and a human constant region. A "humanized antibody is an producing the antibodies and fragments or variants antibody containing complementarity determining regions described herein comprising immunizing mice with a CB1 (CDRs) that are derived from a non-human antibody; and receptor immunogen Such as, for example, CB1 receptor framework regions as well as constant regions that are DNA, CB1 receptor protein, or CB1/lipid complex. In some derived from a human antibody. embodiments, mice are immunized 1, 2, 3, 4, 5, or more 0112. As used herein, the term “CDR' or “complemen times. In some embodiments, mice are immunized with CB1 tarity determining region' means the noncontiguous antigen receptor DNA and the CB1 receptor response is boosted by combining sites found within the variable region of both US 2017/0210797 A1 Jul. 27, 2017 heavy and light chain polypeptides. These particular regions be generated using any human framework sequence, and are have been described by Kabat et al., J. Biol. Chem. 252, also encompassed in the present invention. In one embodi 6609-6616 (1977) and Kabat et al., Sequences of protein of ment, framework sequences suitable for use in the present immunological interest. (1991), and by Chothia et al., J. invention include those framework sequences that are struc Mol. Biol. 196:901-917 (1987) and by MacCallum et al., J. turally similar to the framework sequences provided herein. Mol. Biol. 262:732-745 (1996) where the definitions include In some embodiments, human frameworks were selected overlapping or Subsets of amino acid residues when com based on homology between the parent antibody and the pared against each other. The Kabat definition is based on human germline VH and VK genes. Selected frameworks, in sequence variability. The IMGT unique numbering for all IG Some embodiments, had the highest homology with the and TR V-regions of all species relies on the high conser parent antibody VH and VK genes and also were predicted, vation of the structure of the variable region (Lefranc, Mpet based on computer modeling or other means, to Support the al., Dev comp. Immunol. 27:55-77, 2003). IMGT number CDR structure predicted to be presented by the parent ing, set up after aligning more than 5,000 sequences takes antibody. into account and combines the definition of the framework and CDRs. The Clothia definition is based on the location of 0116 Further modifications in the framework regions the structural loop regions. The Contact definition (MacCa may be made to improve the properties of the antibodies lum et al.) is based on an analysis of the complex crystal provided herein. Such further framework modifications may include chemical modifications; point mutations to reduce structures and antibody-antigen interactions. The amino acid immunogenicity or remove T cell epitopes; or back mutation residues which encompass the CDRs as defined by each of to the residue in the original germline sequence. In one the above cited references are set forth for comparison. In embodiment of the present invention, the humanized anti one embodiment disclosed herein, the term “CDR is a CDR bodies and fragments thereof comprise a human framework as defined by the Kabat definition. In another embodiment and grafted CDRs provided herein, without further modifi disclosed herein, the CDR is a CDR as defined by IMGT. cations to the variable region. Humanized antibodies that do 0113. The CDRs generally are of importance for epitope not comprise a human framework backmutation are herein recognition and antibody binding. However, changes may be termed HO (e.g., P1C4-HO). In another embodiment of the made to residues that comprise the CDRs without interfering present invention, the humanized antibodies and fragments with the ability of the antibody to recognize and to bind the thereof comprise a human framework and grafted CDRs cognate epitope. For example, changes that do not impact provided herein, wherein the amino acid at position 27 epitope recognition, yet increase the binding affinity of the and/or and 28 of the heavy chain framework region 1 is antibody for the epitope, may be made. Several studies have backmutated. In a further embodiment, the amino acid at Surveyed the effects of introducing one or more amino acid position 27 is backmutated from Gly (G) to Tyr (Y); and the changes at various positions in the sequence of an antibody, amino acid at position 28 is backmutated from Thr (T) to based on the knowledge of the primary antibody sequence, Glu (E). Humanized antibodies having such mutations at on the properties thereof, such as binding and level of positions 27 and 28 are herein described as “H2 or “H2 expression (Yang et al., 1995, J Mol Biol 254:392-403; (YE)” (e.g., P1C4-H2 or P1C4-H2 (YE)). In another Rader et al., 1998, Proc Natl Acad Sci USA95:8910-8915; embodiment of the present invention, the humanized anti and Vaughan et al., 1998, Nature Biotechnology 16, 535 bodies and fragments thereof comprise a human framework 539). and grafted CDRs provided herein, wherein the amino acid 0114 Thus, equivalents of an antibody of interest can be at position 27 and/or and 28 of the heavy chain framework generated by changing the sequences of the heavy and light region 1 and the amino acid at position 60 and/or 61 of the chain genes in the CDR1, CDR2 or CDR3, or framework heavy chain framework region 3 is backmutated. In a further regions, using methods such as oligonucleotide-mediated embodiment, the amino acid at position 27 is backmutated site-directed mutagenesis, cassette mutagenesis, error-prone from Gly (G) to Tyr (Y); the amino acid at position 28 is PCR DNA shuffling or mutator-strains of E. coli (Vaughan backmutated from Thr (T) to Glu (E); the amino acid at et al., 1998, Nat Biotech 16:535-539; and Adey et al., 1996, position 60 is backmutated from Ala (A) to Asn (N); and the Chap. 16, pp. 277-291, in Phage Display of Peptides and amino acid at position 61 is backmutated from Gin (Q) to Proteins, eds. Kay et al., Academic Press). The methods of Gly (G). Humanized antibodies having Such mutations at changing the nucleic acid sequence of the primary antibody positions 27, 28, 60, and 61 are herein described as “H4 or can result in antibodies with improved affinity (Gram et al., “H4 (YENG)” (e.g., P1C4-H4 or P1C4-H4 (YENG)). In one 1992, Proc Natl Acad Sci USA 89:3576-3580; Boder et al., embodiment of the present invention, the antibodies and 2000, Proc Natl Acad Sci USA 97: 10701-10705; Davies & antigen binding fragments thereof comprise framework Riechmann, 1996, Immunotech 2:169-179; Thompson et al., modifications such as backmutations in the light chain. For 1996, J Mol Biol 256: 77-88: Short et al., 2002, J Biol Chem example, in one embodiment, the antibodies comprise a 277:16365-16370; and Furukawa et al., 2001, J Biol Chem mutation at position 45 and/or 47 of the light chain frame 276:27622-27628). work region 2. In a further embodiment, the amino acid at 0115 For example, the CB1 antibodies provided herein position 45 is mutated from Arg (R) to Lys (K) and the may comprise CDRs derived from one or more murine amino acid at position 47 is mutated from Leu (L) to Trp antibodies and human framework and constant regions. (W). The present invention also encompasses humanized Thus, in one embodiment, the humanized antibody provided antibodies that bind to CB1 and comprise framework modi herein binds to the same epitope on CB1 as the murine fications corresponding to the exemplary modifications antibody from which the antibody's CDRs are derived. described herein with respect to any suitable framework Exemplary humanized antibodies are provided herein. Addi sequence, as well as other framework modifications that tional humanized CB1 antibodies comprising the heavy and otherwise improve the properties of the antibodies. The CB1 light chain CDRs provided herein, or variants thereof, may antibodies and fragments thereof disclosed herein may be of US 2017/0210797 A1 Jul. 27, 2017 an IgG1, IgG2, IgG3, or IgG4 isotype, or any combination Zumab, dacetuZumab, daclizumab, etaracizumab, mil thereof. The term “isotype” refers to the antibody class atuZumab, oZaneZumab, pinatuZumab vedotin, polatuZumab encoded by the heavy chain constant region genes. In Vedotin, tigatuZumab, VeltuZumab, abituzumab, bococi addition, the heavy chain constant region may be derived Zumab, demcizumab, gevokizumab, poneZumab, ralpanci from any species including, but not limited to, mouse, rat, Zumab, romosozumab, taneZumab, blosozumab, conci rabbit, hamster, guinea pig, primate, llama or human. For Zumab, crenezumab, ibalizumab, ixekiZumab, lebrikizumab, example, in one embodiment, the CB1 antibodies and frag olokizumab, pembrolizumab, Simtuzumab, ulocuplumab, ments thereof of the present invention comprise a human vatelizumab, and samalizumab (see, e.g., SEQ ID NOs: IgG1 Fc constant region. In another embodiment, the CB1 358-432). Any of the Fc modifications known in the art may antibodies and fragments thereof comprise a human IgG2. be applied to the CB1 receptor antibodies provided herein to human IgG4, or hybrid IgG2-IgG4 Fc constant region. alter effector function, antibody half life, or other antibody 0117 II. Effector Functions and Fc Modifications properties. 0118. In some embodiments, present invention provides CB1 antibodies comprising variant Fc regions. The Fc 0119. In one embodiment, the CB1 antibody exhibits region of an antibody is the portion of the antibody that reduced effector function. In a further embodiment, the CB1 binds to Fcy receptors (FcyRs) and the complement mol antibody comprises an IgG4 Fc region having a mutation at ecule C1q. The Fc region plays a role in mediating antibody position 228. In a further embodiment, the amino acid at effector functions. “Effector functions,” as used herein in position 228 is mutated from serine (S) to proline (P) (i.e., connection with antibody Fc, refers to antibody functions S228P). In another embodiment, the CB1 antibody exhibits Such as, for example, C1q binding; complement dependent reduced effector function and comprises an IgG2 Fc region cytotoxicity (CDC); Fc receptor binding; antibody-depen having a mutation at position 330 and/or 331. In a further dent cell-mediated cytotoxicity (ADCC); phagocytosis: embodiment, the amino acid at position 330 is mutated from opSonization; transcytosis; and down-regulation of cell Sur alanine (A) to serine (S), and/or the amino acid at position face receptors (e.g. B cell receptor). Such effector functions 331 is mutated from proline (P) to serine (S). In a further generally require the Fc region to be combined with a embodiment, the CB1 antibody comprises an IgG2 Fc binding domain (e.g. an antibody variable domain) and can domain having both A330S and P331S mutations. In another be assessed using various assays known in the art for embodiment, the CB1 antibody comprises an IgG2/IgG4 evaluating such antibody effector functions. Variant Fc hybrid Fc region. For example, in one embodiment, the CB1 regions are Fc regions that comprise modifications that alter antibody comprises a CH1 and hinge region derived from effector functions. In some embodiments, the CB1 antibod IgG2, and a CH2 and CH3 region derived from IgG4. ies provided herein comprise Fc region modifications that reduce, impair, or eliminate one or more effector functions. I0120 Conformation Antigen Presenting System For example, in one embodiment, the antibodies and frag (iCAPS). iCAPS enable the purified, isolated, conformation ments thereof disclosed herein bind CB1 and exhibit ally correct presentation of functional GPCRs. Purified reduced, impaired, or absent C1q binding and/or CDC GPCRs are stabilized in lipid bilayers surrounded by a belt and/or ADCC. Fc modifications may be amino acid inser protein. tions, deletions, or Substitutions, or may be chemical modi fications. For example, Fc region modifications may be I0121. In one embodiment, the invention provides an made to increase or decrease complement binding; to isolated nucleic acid encoding any one of the antibodies and increase or decrease antibody-dependent cellular cytoxicity; antigen binding fragments or variants thereof disclosed or to modify glycosylation. Various Fc modifications are herein. In some embodiments, a vector comprising the known in the art and have been described, for example, in isolated nucleic acid is provided. In some embodiments, a Labrijin et al., Nature Biotech 27(8):767-71 (2009); Iduso host cell transformed with the vector is provided. In some gie, et al. J. Immunol 2000; Greenwood etal EurJImmunol embodiments, the host cell is a prokaryotic cell. In further 23:1098-104 (1993); Mueller et al. Mol Immunol 1997: embodiments, the host cell is Escherichia coli. In some 34:441-52; and Rother et al Nature Biotechnol 2007: embodiments, the host cell is a eukaryotic cell. In further 25:1256-64. Any of the Fc modifications known in the art embodiments, the eukaryotic cell is selected from the group may be applied to the exemplary CB1 antibodies disclosed consisting of protist cell, animal cell, plant cell and fungal herein to alter effector function. Moreover, various thera cell. In some embodiments, the host cell is a mammalian cell peutic antibodies have been engineered to have Fc region including, but not limited to, 293, COS, NSO, and CHO and; modifications to alter effector function. Such therapeutic or a fungal cell Such as Saccharomyces cerevisiae; or an antibodies are known in the art and include, for example, insect cell such as Sf9. One embodiment of the invention alemtuzumab, benralizumab, bevacizumab, bimekizumab, provides methods of producing the antibodies and fragments cantuzumab, codrituzumab, dalotuZumab, efalizumab, elo or variants described herein comprising culturing any one of tuZumab, enavatuZumab, enokizumab, etrolizumab, farletu Zumab, ficlatuZumab, imgatuZumab, itolizumab, lifastu the host cells also herein in a culture medium under condi Zumab, ligelizumab, lodelcizumab, lorVotuZumab, tions sufficient to produce the binding protein. mogamulizumab, motavizumab, obinutuZumab, ocaratu 0.122 Exemplary CB1 receptor binding antibodies of the Zumab, omalizumab, parsatuZumab, pateclizumab, peraki invention are provided below in Table 1. Additional exem Zumab, pertuzumab, pidilizumab, quilizumab, rontalizumab, plary CB1 receptor binding antibodies of the invention are SofituZumab, SolaneZumab, Suvizumab, teplizumab. tildraki defined by SEQID NO and provided in the sequence listing Zumab, tocilizumab, trastuzumab, trastuzumab emtansine, as shown in Table 2. Sequences for the exemplary human tregalizumab, Vcodolizumab, VorsetuZumab, VorsetuZumab ized CB1 receptor binding antibodies of the invention are mafodotin, yttrium (90Y) elivatuzumab tetraxetan, anrukin provided in Table 3. US 2017/0210797 A1 Jul. 27, 2017 24 TABLE 1 - continued Nucleic acid and amino acid sequences of heavy chain variable regions and light chain variable regions of exemplary CB1 receptor binding antibodies SEQ Sequence ID Name description NO Sequence LC constant 64 RTVAAPSVFIFPPSDEOLKSGTASVWCLLNNFYPREAKV region QWKVDNALOSGNSOESVTEODSKDSTYSLSSTLTLSKA amino acid DYEKHKWYACEVTHOGLSLPVTKSFNRGEC sequence TABLE 2 TABLE 2-continued SEQ ID NOS for additional CB1 receptor binding antibodies SEQ ID NOS for additional CB1 receptor binding antibodies SEQ SEQ Name Sequence description ID NO Name Sequence description ID NO PA2LR3-P1G6 (chimeric) Heavy chain (HC) variable nucleic 65 HC constant region nucleic acid O7 acid HC constant region amino acid O8 HC variable region amino acid 66 Light chain (LC) variable region 09 HC constant region nucleic acid 67 nucleic acid HC constant region amino acid 68 LC variable region amino acid 10 Light chain (LC) variable region 69 LC constant region nucleic acid 11 nucleic acid LC constant region amino acid 12 LC variable region amino acid 70 PA2LR3-P3B8 (chimeric) Heavy chain (HC) variable nucleic 13 LC constant region nucleic acid 71 acid LC constant region amino acid 72 HC variable region amino acid 14 PA2LR3-P1H4 (chimeric) Heavy chain (HC) variable nucleic 73 HC constant region nucleic acid 15 acid HC constant region amino acid 16 HC variable region amino acid 74 Light chain (LC) variable region 17 HC constant region nucleic acid 75 nucleic aci HC constant region amino acid 76 LC variable region amino acid 18 Light chain (LC) variable region 77 LC constant region nucleic acid 19 nucleic acid LC constant region amino acid 2O LC variable region amino acid 78 PA2LR3-P3F8 (chimeric) Heavy chain (HC) variable nucleic 21 LC constant region nucleic acid 79 acid LC constant region amino acid 8O HC variable region amino acid 22 PA2LR3-P2B8 (chimeric) Heavy chain (HC) variable nucleic 81 HC constant region nucleic acid 23 acid HC constant region amino acid 24 HC variable region amino acid 82 Light chain (LC) variable region 25 HC constant region nucleic acid 83 nucleic aci HC constant region amino acid 84 LC variable region amino acid 26 Light chain (LC) variable region 85 LC constant region nucleic acid 27 nucleic aci LC constant region amino acid 28 LC variable region amino acid 86 PA2LR3-P4C6 (chimeric) Heavy chain (HC) variable nucleic 29 LC constant region nucleic acid 87 acid LC constant region amino acid 88 HC variable region amino acid 30 PA2LR3-P2E.5 (chimeric) Heavy chain (HC) variable nucleic 89 g acid HC constan region nucleic acid 31 HC variable region amino acid 90 HC constan region amino acid 32 HC constant region nucleic acid 91 Light chain (LC) variable region 33 HC constant region amino acid 92 nucleic acid Light chain (LC) variable region 93 LC variable region amino acid 34 nucleic acid LC constant region nucleic acid 35 LC variable region amino acid 94 LC constant region amino acid 36 LC constant region nucleic acid 95 PA2LR3-P4G10 (chimeric) Heavy chain (HC) variable nucleic 37 LC constant region amino acid 96 acid PA2LR3-P3A8 (chimeric) Heavy chain (HC) variable nucleic 97 HC variable region amino acid 38 acid HC constant region nucleic acid 39 HC variable region amino acid 98 HC constant region amino acid 40 HC constant region nucleic acid 99 Light chain (LC) variable region 41 HC constant region amino acid 100 nucleic acid Light chain (LC) variable region 101 LC variable region amino acid 42 nucleic acid LC constant region nucleic acid 43 LC variable region amino acid 102 LC constant region amino acid 44 LC constant region nucleic acid 103 PA2LR3-P5E7 (chimeric) Heavy chain (HC) variable nucleic 45 LC constant region amino acid 104 acid PA2LR3-P3B10 (chimeric) Heavy chain (HC) variable nucleic 105 HC variable region amino acid 46 acid HC constant region nucleic acid 47 HC variable region amino acid 106 HC constant region amino acid 48 US 2017/0210797 A1 Jul. 27, 2017 25 TABLE 2-continued TABLE 2-continued SEQ ID NOS for additional CB1 receptor binding antibodies SEQ ID NOS for additional CB1 receptor binding antibodies SEQ SEQ Name Sequence description ID NO Name Sequence description ID NO Light chain (LC) variable region 49 LC variable region amino acid 2O6 nucleic aci LC constant region nucleic acid 2O7 LC variable region amino acid 50 LC constant region amino acid 208 LC constant region nucleic acid 51 PA13R3-P3F6 (chimeric) Heavy chain (HC) variable nucleic 209 LC constant region amino acid 52 acid PA2LR3-P6D7 (chimeric) Heavy chain (HC) variable nucleic 53 HC variable region amino acid 210 acid HC constant region nucleic acid 211 HC variable region amino acid S4 HC constant region amino acid 212 HC constant region nucleic acid 55 Light chain (LC) variable region 213 HC constant region amino acid 56 nucleic acid Light chain (LC) variable region 57 LC variable region amino acid 214 nucleic acid LC constant region nucleic acid 215 LC variable region amino acid 58 LC constant region amino acid 216 LC constant region nucleic acid 59 PA13R3-P4C4 (chimeric) Heavy chain (HC) variable nucleic 217 LC constant region amino acid 60 acid PA2R3-P1A7 (chimeric) Heavy chain (HC) variable nucleic 61 HC variable region amino acid 218 acid HC constant region nucleic acid 219 HC variable region amino acid 62 HC constant region amino acid 220 HC constant region nucleic acid 63 Light chain (LC) variable region 221 HC constant region amino acid 64 nucleic aci Light chain (LC) variable region 65 LC variable region amino acid 222 nucleic acid LC constant region nucleic acid 223 LC variable region amino acid 66 LC constant region amino acid 224 LC constant region nucleic acid 67 PA13R3-P4F8 (chimeric) Heavy chain (HC) variable nucleic 225 LC constant region amino acid 68 acid PA2R3-P1 F1 (chimeric) Heavy chain (HC) variable nucleic 69 HC variable region amino acid 226 aci HC constant region nucleic acid 227 HC variable region amino acid 70 HC constant region amino acid 228 HC constant region nucleic acid 71 Light chain (LC) variable region 229 HC constant region amino acid 72 nucleic acid Light chain (LC) variable region 73 LC variable region amino acid 230 nucleic aci LC constant region nucleic acid 231 LC variable region amino acid 74 LC constant region amino acid 232 LC constant region nucleic acid 75 PA13R3-P4G 11 (chimeric) Heavy chain (HC) variable nucleic 233 LC constant region amino acid 76 acid PA13R3-P3A7 (chimeric) Heavy chain (HC) variable nucleic 77 HC variable region amino acid 234 aci HC constant region nucleic acid 235 HC variable region amino acid 78 HC constant region amino acid 236 HC constant region nucleic acid 79 Light chain (LC) variable region 237 HC constant region amino acid 8O nucleic aci Light chain (LC) variable region 81 LC variable region amino acid 238 nucleic acid LC constant region nucleic acid 239 LC variable region amino acid 82 LC constant region amino acid 240 LC constant region nucleic acid 83 PA13R3-P4H10 (chimeric) Heavy chain (HC) variable nucleic 241 LC constant region amino acid 84 acid PA13R3-P3C3 (chimeric) Heavy chain (HC) variable nucleic 85 HC variable region amino acid 242 acid HC constant region nucleic acid 243 HC variable region amino acid 86 HC constant region amino acid 244 HC constant region nucleic acid 87 Light chain (LC) variable region 245 HC constant region amino acid 88 nucleic aci Light chain (LC) variable region 89 LC variable region amino acid 246 nucleic acid LC constant region nucleic acid 247 LC variable region amino acid 90 LC constant region amino acid 248 LC constant region nucleic acid 91 PA15R3-P3A6 (chimeric) Heavy chain (HC) variable nucleic 249 LC constant region amino acid 92 acid PA13R3-P3D10 (chimeric) Heavy chain (HC) variable nucleic 93 HC variable region amino acid 250 acid HC constant region nucleic acid 251 HC variable region amino acid 94 HC constant region amino acid 252 HC constant region nucleic acid 95 Light chain (LC) variable region 253 HC constant region amino acid 96 nucleic acid Light chain (LC) variable region 97 LC variable region amino acid 254 nucleic acid LC variable region9. amino acid 98 LC constant region nucleic acid 255 LC constant region nucleic acid 99 LC constan region amino acid 256 LC constant region amino acid 200 PA15R3-P3A7 (chimeric) Heavy chain (HC) variable nucleic 257 PA13R3-P3D11 (chimeric) Heavy chain (HC) variable nucleic 2O1 acid acid HC variable region amino acid 258 HC variable region amino acid 2O2 HC constant region nucleic acid 259 HC constant region nucleic acid 2O3 HC constant region amino acid 260 HC constant region amino acid 204 Light chain (LC) variable region 261 Light chain (LC) variable region 205 nucleic acid nucleic acid LC variable region amino acid 262 US 2017/0210797 A1 Jul. 27, 2017 26 TABLE 2-continued TABLE 2-continued SEQ ID NOS for additional CB1 receptor binding antibodies SEQ ID NOS for additional CB1 receptor binding antibodies SEQ SEQ Name Sequence description ID NO Name Sequence description ID NO LC constant region nucleic acid 263 Light chain (LC) variable region 301 LC constant region amino acid 264 nucleic aci PA15R3-P3C9 (chimeric) Heavy chain (HC) variable nucleic 26S LC variable region amino acid 3O2 acid LC constant region nucleic acid 303 HC variable region amino acid 266 LC constant region amino acid 304 HC constant region nucleic acid 267 PA16R3-P1 H5 (chimeric) Heavy chain (HC) variable nucleic 305 HC constant region amino acid 268 acid Light chain (LC) variable region 269 HC variable region amino acid 306 nucleic acid HC constant region nucleic acid 307 LC variable region amino acid 270 HC constant region amino acid 3O8 LC constant region nucleic acid 271 Light chain (LC) variable region 309 LC constant region amino acid 272 nucleic acid PA16R3-P2G6 (chimeric) Heavy chain (HC) variable nucleic 273 LC variable region amino acid 310 acid LC constant region nucleic acid 311 HC variable region amino acid 274 LC constant region amino acid 312 HC constant region nucleic acid 275 PA18R3-P1 D8 (chimeric) Heavy chain (HC) variable nucleic 313 HC constant region amino acid 276 acid Light chain (LC) variable region 277 HC variable region amino acid 314 nucleic acid HC constant region nucleic acid 315 LC variable region amino acid 278 HC constant region amino acid 316 LC constant region nucleic acid 279 Light chain (LC) variable region 317 LC constant region amino acid 28O nucleic acid PA16R3-P1A6 (chimeric) Heavy chain (HC) variable nucleic 281 LC variable region amino acid 3.18 acid LC constant region nucleic acid 319 HC variable region amino acid 282 LC constant region amino acid 320 HC constant region nucleic acid 283 PA18R3-P1 E5 (chimeric) Heavy chain (HC) variable nucleic 321 HC constant region amino acid 284 acid Light chain (LC) variable region 285 HC variable region amino acid 322 nucleic aci HC constant region nucleic acid 323 LC variable region amino acid 286 HC constant region amino acid 324 LC constant region nucleic acid 287 Light chain (LC) variable region 325 LC constant region amino acid 288 nucleic acid PA16R3-P1B5 (chimeric) Heavy chain (HC) variable nucleic 289 LC variable region amino acid 326 acid LC constant region nucleic acid 327 HC variable region amino acid 290 LC constant region amino acid 328 HC constan region nucleic acid 291 PA18R3-P1 H5 (chimeric) Heavy chain (HC) variable nucleic 329 HC constant region amino acid 292 acid Light chain (LC) variable region 293 HC variable region amino acid 330 nucleic acid LC variable region9. amino acid 294 HC constant region nucleic acid 331 LC constant region nucleic acid 295 HC constant region amino acid 332 LC constant region amino acid 296 Light chain (LC) variable region 333 PA16R3-P1 E5 (chimeric) Heavy chain (HC) variable nucleic 297 nucleic acid acid LC variable region amino acid 334 HC variable region amino acid 298 LC constant region nucleic acid 335 HC constant region nucleic acid 299 LC constant region amino acid 336 HC constant region amino acid 300 TABL 3 Sequences of exemplary humanized antibodies Name/ SEQ sequence ID description NO Sequence Humanized 337 EIWLTOSPATLSLSPGERATLSCRASOSVSSSYLHWYOOKPGQAPRILLIYS P1C4 light TSNLASGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCHOYHRSPPTFGOGT chain KWEIK variable region Humanized 338 EIWLTOSPATLSLSPGERATLSCRASOSVSSSYLHWYOOKPGQAPRILLIYS P1C4 full TSNLASGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCHOYHRSPPTFGOGT light chain KVEIKRTVAAPSVFIFPPSDEOLKSGTASVWCLLNNFYPREAKVOWKVDN ALOSGNSOESVTEODSKDSTYSLSSTLTLSKADYEKHKWYACEVTHOGLS US 2017/0210797 A1 Jul. 27, 2017 28 TABLE 3 - continued Sequences of exemplary humanized antibodies Name/ SEQ sequence ID description NO Sequence TYTCNWDHKPSNTKVDKTVERKCCVECPPCPAPPWAGPSWFLPPKPKDT LMISRTPEVTCVVVDVSHEDPEVOFNWYWDGVEVHNAKTKPREEOFNST FRVVSVLTVWHODWLNGKEYKCKVSNKGLPSSIEKTISKTKGOPREPOVY TLPPSREEMTKNOWSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPMLD SDGSFFLYSKLTVDKSRWOOGNWFSCSVMHEALHNHYTOKSLSLSPGK Humanized 348 OVOLVOSGAEWKKPGSSVKVSCKASGYEFSYYWMNWVROAPGOGLEW P1C4 H2 MGOIYPGDGETKYAOKFOGRVTITADKSTSTAYMELSS LRSEDTAWYYC IgG4S228P ARSHGNYLPYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSWWTVPSSSLGTKT YTCNWDHKPSNTKWDKRWESKYGPPCPPCPAPEFLGGPSWFLFPPKPKDTL MISRTPEVTCVVVDVSOEDPEVOFNWYWDGVEVHNAKT KPREEOFNSTY RVVSVLTVLHODWLNGKEYKCKVSNKGLPSSIEKTISKAKGOPREPOVYT LPPSOEEMTKNOWSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS KSLSLSIGK Humanized 349 OVOLVOSGAEWKKPGSSVKVSCKASGYEFSYYWMNWVROAPGOGLEW P1C4 H4 MGOIYPGDGETKYNGKFOGRVTITADKSTSTAYMELSS LRSEDTAWYYC IgG2-4 ARSHGNYLPYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV Hybrid KDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSWWTVPSSNFGTO KTWERKCCWECPPCPAPEFLGG PSWFLFPPKPKD TLMISRTPEVTCVVVDVSOEDPEVOFNWYWDGVEVHNA KTKPREEOFNS TYRVVSVLTVLHODWLNGKEYKCKVSNKGLPSSIEKTISKAKGOPREPOV YTLPPSOEEMTKNOWS LTCLVKGFYPSDIAVEWESNGO PENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNWFSCSVMHEALHNHYTOKSLSLSLGK Humanized 35O OVOLVOSGAEWKKPGSSVKVSCKASGYEFSYYWMNWVROAPGOGLEW P1C4 H4 MGOIYPGDGETKYNGKFOGRVTITADKSTSTAYMELSS RSEDTAVYYC IgG2A33OS/ ARSHGNYLPYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSWWTVPSSNFGTO P331S TYTCNWDHKPSNTKVDKTVERKCCVECPPCPAPPWAGPSWFLPPKPKDT LMISRTPEVTCVVVDVSHEDPEVOFNWYWDGVEVHNAKT KPREEOFNST FRVVSVLTVWHODWLNGKEYKCKVSNKGLPSSIEKTTSKTKGOPREPOVY TLPPSREEMTKNOWSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPMLD SDGSFFLYSKLTVDKSRWOOGNWFSCSVMHEALHNHYTO KSLSLSPGK Humanized 351 OVOLVOSGAEWKKPGSSVKVSCKASGYEFSYYWMNWVROAPGOGLEW P1C4 H4 MGOIYPGDGETKYNGKFOGRVTITADKSTSTAYMELSSL RSEDTAVYYC IgG4S228P ARSHGNYLPYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSWWTVPSSSLGTKT YTCNWDHKPSNTKWDKRWESKYGPPCPPCPAPEFLGGPSWFLFPPKPKDTL MISRTPEVTCVVVDVSOEDPEVOFNWYWDGVEVHNAKTK PREEOFNSTY RVVSVLTVLHODWLNGKEYKCKVSNKGLPSSIEKTISKA KGOPREPOVYT LPPSOEEMTKNOWSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNWFSCSVMHEALHNHYTOKSLSLSLGK 0123. In some embodiments, the anti-CB1 receptor anti Subject for therapeutic purposes. In some embodiments, bodies provided herein comprise the sequences provided methods of treatment comprising administering the antibod herein or conservative variants thereof. "Conservative vari ies and binding fragments or variants thereof disclosed ants, as used herein, include conservative amino acid herein to a Subject. substitutions, insertions, or deletions. The person of skill in I0126. In certain embodiments, methods are provided for the art will recognize that a conservative amino acid Sub treatment of diseases wherein the peripheral CB1 receptors stitution is a Substitution of one amino acid with another are preferentially targeted. “Peripheral CB1 receptors', as amino acid that has a similar structural or chemical proper defined herein, are those CB1 receptors that are not localized ties, such as, for example, a similar side chain; and a to the brain or central nervous system (e.g. peripherally conservative amino acid substitution, insertion or deletion restricted CB1 receptors). In contrast, the term “global CB1 results in a sequence that retains the biological activity of the receptors' refers to CB1 receptors anywhere in the body, reference sequence. Exemplary conservative Substitutions including the brain and CNS. are described in the art, for example, in Watson et al., Molecular Biology of the Gene, The Bengamin/Cummings 0127. In one embodiment, the isolated antibodies and antigen binding fragments thereof are useful in the treatment Publication Company, 4" Ed. (1987). of various diseases or disorders such as, for example, 0.124 III. Methods of Treating CB1-Associated Disor obesity, diabetes, dyslipidemia, fibrosis, non-alcoholic Ste ders atohepatitis (NASH), liver diseases, primary biliary cirrho 0.125. The antibodies and antigen binding fragments sis, cardiovascular disease, cancer, pain, multiple Sclerosis thereof disclosed herein can be administered to a human (MS) spasticity, glaucoma, inflammatory diseases, neph US 2017/0210797 A1 Jul. 27, 2017 29 ropathies, osteoporosis, metabolic disorders, psychiatric dis 1228). Selective knockdown of CB1 using a macrophage orders, neurological disorders, neurodegenerative disorders, specific CB1 knockdown siRNA (CB1R-GeRPs) prevents reproductive disorders, renal disease, kidney fibrosis, progressive hyperglycemia and decline in plasma insulin chronic kidney disease, atherosclerosis, cancer, and skin and C-peptide in Zucker diabetic fatty (ZDF) rats, which are disorders, among others. a common model for T2D insulin resistance, hyperglycemia 0128. CB1 receptor signaling has been shown to exhibit and beta cell failure. (Jourdan et al., 2013, Nature Med. detrimental activity in, for example, obesity, diabetes, fibro 19(9): 1132-1140) In a mouse model of alcohol-induced liver sis, liver diseases, cardiovascular disease, and cancer. (Ku steatosis, both global CB1 knockout (CB1-/-) and hepato nos et al., 2009, Trends Pharmacol Sci 30:1-7.) In one cyte-specific CB1 knockout (LCB1-/-) have reduced steato aspect, the anti-CB1 antibodies, or fragments thereof, dis sis and increased liver function, thus demonstrating a role of closed herein are useful for antagonizing CB1 activity. CB1 in peripheral cell type (hepatocytes) relevant to steato Accordingly, in another aspect, the invention provides meth sis disease pathology. (Jeong, et al., 2008, Cell Metabolism, ods for treating CB1-associated diseases or disorders by 7:227-235). Lipid accumulation was shown to be reduced in administering to a subject in need of thereof a pharmaceu epididymal white adipose cell lines generated from CB1 tical composition comprising one or more anti-CB1 anti knockout mice relative to wild-type control (Wagner et al., bodies, or antigen binding fragments thereof disclosed 2011, Nutrition and Diabetes, 1:e 16). herein. In some embodiments, the antagonistic CB1 receptor (0132 Studies in different models of disease in mouse antibodies and fragments thereof provided herein provide a have shown that peripherally-restricted CB1 receptor small beneficial effect when used as a treatment for, or for pre molecule antagonists can effectively inhibit liver fibrosis vention of obesity, diabetes, fibrosis, liver diseases, cardio progression. (See, e.g., Wei et al., 2014, Exp. Biol. Med. vascular diseases, addictions such as nicotine addiction, or 239(2):183-192: Tam et al., 2010, J. Clin. Invest. 120(8): CaCCS. 2953-66: Wan et al., 2014, Cell Metabolism, 19(6):900-1: 0129 Nonalcoholic steatohepatitis (NASH), also known Takano et al., 2014, Synapse, 68:89-97.) Non-limiting as nomalcoholic fatty liver disease (NAFLD), refers to the examples of known CB1 antagonists include rimonabant, accumulation of hepatic steatosis not due to excess alcohol taranabant, VD60, Isis-414930 Antisense CB1, JD5037, consumption. NASH is a liver disease characterized by AM6545, and TM38837. CB1 antagonists such as rimona inflammation of the liver with concurrent fat accumulation. bant have been shown to inhibit cell proliferation and NASH is also frequently found in people with diabetes and down-regulate pro-fibrotic gene expression in primary obesity and is related to metabolic syndrome. NASH is the human hepatic stellate cells (HSC), which mediate fibrosis progressive form of the relatively benign non-alcoholic fatty by transitioning into myofibroblasts (Patsenker et al., 2011, liver disease, for it can slowly worsen causing fibrosis Mol Med., 17(11-12): 1285-1294). In the CC1-induced liver accumulation in the liver, which leads to cirrhosis (reviewed fibrosis mouse model, CB1 antagonist VD60 (3.4.22-3- in Smith, et al., 2011, Crit Rev Clin Lab Sci., 48(3): 97-113). demethoxycarbonyl-3-hydroxylmethyl-4-deacetyl-Vindo Currently, no specific therapies for NASH exist. line 3,4-thionocarbonate) was demonstrated to inhibit pro 0130. In one aspect, the anti-CB1 antibodies or fragments duction of pro-fibrotic gene expression (alpha collagen) and thereof disclosed herein are used in the treatment, preven proliferation in activated hepatic stellate cells (HSC line tion, detection, or study of fibrosis. Several studies in mouse LX-2), while selective CB1 agonist ACEA (N-(2-chloro models have confirmed the role of CB1 receptor in fibrosis, ethyl)-5Z,8Z., 11Z.14Z-eicosatetraenamide) prevented this including liver fibrosis. (See, e.g., Wei et al., 2014, Exp. effect (Wei Y. et al., 2014, Exp. Biol. Med. 239(2):183-192). Biol. Med. 239(2):183-192: Tam et al., 2010, J. Clin. Invest. CB1 antagonist JD5037 has been shown to reverse endo 120(8):2953-66: Wan et al., 2014, Cell Metabolism, 19(6): cannabinoid-induced inhibition of insulin signaling. (Cinar 900-1: Takano et al., 2014, Synapse, 68:89-97). Peripheral et al., 2014, Hepatology, 59(1) 143-153). CB1 blockade CB1 has been implicated in several mechanisms contribut using rimonabant reverses inflammation-induced impair ing to NASH and liver fibrosis, including steatosis (fatty ment of glucose uptake in adipocytes isolated from high-fat liver), inflammation, and liver injury (reviewed by Mallat et diet rats (Miranville et al., 2010, Obesity 18: 2247-2254). al., 2013, J Hepatology, 59(4):891-896). CB1 has been 0.133 Human studies also link peripheral CB1 receptors demonstrated to be up-regulated in activated human hepatic to disease etiology and progression. For example, up-regu stellate cells (HSC), which mediate fibrosis by transitioning lation of CB1 in liver of NASH and HCV patients correlated into myofibroblasts. (Teixeira-Clere et al., 2006, Nature with severity of liver steatosis and fibrosis. (Auguet et al., Med., 12(6):671-76). CB1 has also been implicated in 2014, BioMed Res. Intl. Vol. 2014, Article ID 502542). In diabetic nephropathy. Lin et al., 2014 J. Mol. Med. 92(7): addition, chronic CB1 agonism (via cannabis use) correlated 779-92.) with increased severity of liver steatosis and fibrosis in HCV 0131 Studies in hepatocyte-specific and global CB1 patients. (Van der Poorten et al., 2010, PlosOne 5, e12841) knockout mice have implicated a major role of CB1 in Furthermore, it has been shown that CB1 blockade in obese peripheral cell type (hepatocytes) relevant to several meta patients improves liver steatosis. (Despres et al., 2009, bolic diseases and disorders. In a mouse model of diet Arterioscler Thromb Vasc Biol. 29:416–423). induced obesity, both global CB1 knockout (CB1-/-) and I0134. It will also be recognized that the effect of CB1 hepatocyte-specific CB1 knockout (LCB1-/-) demonstrated antagonism differs depending on the location of the receptor. reduced steatosis (fatty liver) and increased liver function, For instance, it is known that the effects of CB1 antagonism thus demonstrating a role of CB1 in peripheral cell type are tissue specific, as beneficial cardiometabolic effects of (hepatocytes) relevant to non-alcoholic Steatohepatitis rimonabant observed in patients are independent of weight (NASH), diabetes, and metabolic syndrome disease patholo loss. (Pi-Sunyer et al., 2006, JAm Coil Cardio. 147: 362A). gies. (Osei-Hyiaman et al., 2008, J. Clin. Invest., 118(9): Furthermore, it is known that rimonabant improves glyce 3160-3169; Liu et al., 2012, Gastroenterology, 142:1218 mic control in type 2 diabetes patients, (see, e.g., Hollander US 2017/0210797 A1 Jul. 27, 2017 30 et al., 2010, Diabetes Care. 33(3):605-7) but that this effect combination therapy wherein human antibodies are admin is accompanied by significant psychiatric side effects istered to a Subject with another therapeutic agent, such as imparted by CB1 receptors located in the CNS. (Kunos et al. one or more additional antibodies that bind other targets 2009, Trends Pharmacol Sci 30:1-7: Moreira et al., 2009, (e.g., antibodies that bind other cytokines or that bind cell Rev Bras Psiquiatr. 31(2): 145-53; Pacher et al., 2013, FEBS Surface molecules). Because signaling pathway redundan J. 280(9): 1918-1943.) The CB1 receptor antagonistrimona cies can result in lack of response to a single antibody, bant was shown to improve the profile of several metabolic diverse strategies to use combination therapy with antibod risk factors (including adiponectin levels) in overweight ies that bind to different epitopes or different antigens on the patients according to the Rimonabant in Obesity-Lipids same target cell have been proposed. Combinations such as (RIO-Lipids) study. (See, e.g., Despres et al., 2005, N Engl anti-CD20 and anti-CD22 (Stein et al., Clin Cancer Res J Med, 353:2121-2134). 2004, 10:2868-2878), anti-CD20 and anti-HLA-DR (Tobin 0135 CB1 receptor signaling has been shown to exhibit et al., Leuk Lymphoma 2007, 48:944-956), anti-CD20 and beneficial activity in and pain, MS spasticity, and glaucoma, anti-TRAIL-R1 (Maddipatla et al., Clin Cancer Res 2007, among others. (Pacher et al., 2013, FEBS J. 280(9):1918 13:4556-4564), anti-IGF-1R and anti-EGFR (Goetsche et 1943). In some embodiments, the agonistic CB1 receptor al., Int J Cancer 2005, 113:316-328), anti-IGF-1R and antibodies and fragments thereof provided herein provide a anti-VEGF (Shang et al., Mol Cancer Ther 2008, 7:2599 beneficial effect when used as a treatment for, or for pre 2608), or trastuzumab and pertuzumab that target different vention of pain, MS spasticity, or glaucoma. CB1 agonists regions of human EGFR2 (Nahta et al., Cancer Res 2004, have been demonstrated to activate liver fatty acid synthesis, 64:2343-2346) have been evaluated preclinically, showing gluconeogenesis, and other metabolic pathways. (See, e.g., enhanced or synergistic antitumor activity in vitro and in Osei-Hyiaman et al., 2005, J. Clin. Invest., 115(5):1298 vivo. Such combination therapies may advantageously uti 1305; Chanda et al., 2012, JBC, 287(45):38041-38049). lize lower dosages of the administered therapeutic agents, 0136. Multiple Sclerosis (MS) spasticity refers to feel thus avoiding possible toxicities or complications associated ings of stiffness and a wide range of involuntary muscle with the various monotherapies. spasms (Sustained muscle contractions or Sudden move 0140. The antibodies and fragments disclosed herein can ments). Spasticity is one of the more common symptoms of be administered in combination with any desired therapeutic MS, and can vary in degree from mild tightness to painful, agent. In certain embodiments, the antibodies and fragments uncontrollable spasms of extremities. Left untreated, spas disclosed herein are administered in combination with, for ticity can lead to serious complications, including contrac example, a LOXL2 antibody, TGFB antibody, nintedanib, tures (frozen or immobilized joints) and pressure Sores. tyrosine kinase inhibitor, PPAR agonist, Farnesoid X recep Current treatment options for MS spasticity include tor (FXR) agonist, glucagon-like peptide 1 receptor agonist, baclofen, tizanidine, diazepam, dantrolene, phenol, among or caspase inhibitor. others. CB1 receptors have been shown to mediate control 0141 IV. Pharmaceutical Compositions of spasticity in a mouse model of MS. (Pryce et al., 2007, Br 0142. In another aspect, the invention provides pharma J Pharmacol. 150(4): 519-525). ceutical compositions comprising an anti-CB1 antibody, or 0.137 Activation of CB1 receptors produces analgesic fragment thereof. effects in several experimental pain models, including vis 0.143 Methods of preparing and administering antibod ceral pain arising from the gastrointestinal tract. CB1 ago ies, or fragments thereof, disclosed herein to a subject are nists such as WIN55.212-2 and SAB-378 have also been well known to or are readily determined by those skilled in shown to inhibit pain-related responses to repetitive noxious the art. The route of administration of the antibodies, or stimuli (Brusberg et al., 2009, J. Neuroscience, 29(5):1554 fragments thereof, disclosed herein may be oral, parenteral, 1564: Talwar et al., 2011, CNS Neurol Disord Drug Targets. by inhalation or topical. The term parenteral as used herein 10(5):536-44.) includes intravenous, intraarterial, intraperitoneal, intramus 0.138. One skilled in the art would be able, by routine cular, Subcutaneous, rectal or vaginal administration. The experimentation, to determine what an effective, non-toxic intravenous, intraarterial, Subcutaneous and intramuscular amount of antibody (or additional therapeutic agent) would forms of parenteral administration can be used in certain be for the purpose of treating a CB1-associated disease or embodiments. While all these forms of administration are disorder. For example, a therapeutically active amount of a clearly contemplated as being within the scope disclosed polypeptide may vary according to factors such as the herein, a form for administration would be a solution for disease stage (e.g., stage I Versus stage IV), age, sex, medical injection, in particular for intravenous or intraarterial injec complications (e.g., immunosuppressed conditions or dis tion or drip. Usually, a suitable pharmaceutical composition eases) and weight of the subject, and the ability of the for injection may comprise a buffer (e.g. acetate, phosphate antibody to elicit a desired response in the subject. The or citrate buffer), a Surfactant (e.g. polysorbate), optionally dosage regimen may be adjusted to provide the optimum a stabilizer agent (e.g. human albumin), etc. However, in therapeutic response. For example, several divided doses other methods compatible with the teachings herein, the may be administered daily, or the dose may be proportion polypeptides can be delivered directly to the site of the ally reduced as indicated by the exigencies of the therapeutic adverse cellular population thereby increasing the exposure situation. Generally, however, an effective dosage is of the diseased tissue to the therapeutic agent. expected to be in the range of about 0.05 to 100 milligrams 0144 Preparations for parenteral administration include per kilogram body weight per day and in an embodiment sterile aqueous or non-aqueous solutions, Suspensions, and from about 0.5 to 10, milligrams per kilogram body weight emulsions. Examples of non-aqueous solvents are propylene per day. glycol, polyethylene glycol, vegetable oils such as olive oil, 0139. In some embodiments, the anti-CB1 antibodies and and injectable organic esters such as ethyl oleate. Aqueous fragments disclosed herein are used in methods utilizing a carriers include water, alcoholic/aqueous Solutions, emul US 2017/0210797 A1 Jul. 27, 2017 sions or Suspensions, including saline and buffered media. In 0146 Effective doses of the stabilized antibodies, or the Subject invention, pharmaceutically acceptable carriers fragments thereof, disclosed herein, for the treatment of the include, but are not limited to, 0.01-0.1M (e.g. 0.05M) above described conditions vary depending upon many phosphate buffer or 0.8% saline. Other common parenteral different factors, including means of administration, target vehicles include sodium phosphate solutions, Ringer's dex site, physiological state of the patient, whether the patient is trose, dextrose and sodium chloride, lactated Ringers, or human or an animal, other medications administered, and fixed oils. Intravenous vehicles include fluid and nutrient whether treatment is prophylactic or therapeutic. Usually, replenishers, electrolyte replenishers, such as those based on the patient is a human, but non-human mammals including Ringer's dextrose, and the like. Preservatives and other transgenic mammals can also be treated. Treatment dosages additives may also be present such as for example, antimi may be titrated using routine methods known to those of crobials, antioxidants, chelating agents, and inert gases and skill in the art to optimize safety and efficacy. the like. More particularly, pharmaceutical compositions 0147 For passive immunization with an antibody dis closed herein, the dosage may range, e.g., from about 0.0001 Suitable for injectable use include sterile aqueous solutions to 100 mg/kg, and more usually 0.01 to 5 mg/kg (e.g., 0.02 (where water soluble) or dispersions and sterile powders for mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 2 the extemporaneous preparation of sterile injectable solu mg/kg, etc.), of the host body weight. For example dosages tions or dispersions. In Such cases, the composition must be can be 1 mg/kg body weight or 10 mg/kg body weight or sterile and should be fluid to the extent that easy syringabil within the range of 1-10 mg/kg, or in particular embodi ity exists. It should be stable under the conditions of ments at least 1 mg/kg. Doses intermediate in the above manufacture and storage and will in an embodiment be ranges are also intended to be within the scope disclosed preserved against the contaminating action of microorgan herein. isms, such as bacteria and fungi. The carrier can be a solvent 0148 Subjects can be administered such doses daily, on or dispersion medium containing, for example, water, etha alternative days, weekly or according to any other schedule nol, polyol (e.g., glycerol, propylene glycol, and liquid determined by empirical analysis. An exemplary treatment polyethylene glycol, and the like), and Suitable mixtures entails administration in multiple dosages over a prolonged thereof. The proper fluidity can be maintained, for example, period, for example, of at least six months. Additional by the use of a coating Such as lecithin, by the maintenance exemplary treatment regimens entail administration once of the required particle size in the case of dispersion and by per every two weeks or once a month or once every 3 to 6 the use of surfactants. Prevention of the action of microor months. Exemplary dosage schedules include 1-10 mg/kg or ganisms can be achieved by various antibacterial and anti 15 mg/kg on consecutive days, 30 mg/kg on alternate days fungal agents, for example, parabens, chlorobutanol, phenol, or 60 mg/kg weekly. In some methods, two or more mono ascorbic acid, thimerosal and the like. In certain embodi clonal antibodies with different binding specificities are ments, isotonic agents are included, for example, Sugars, administered simultaneously, in which case the dosage of polyalcohols, such as mannitol, Sorbitol, or Sodium chloride each antibody administered may fall within the ranges in the composition. Prolonged absorption of the injectable indicated. compositions can be brought about by including in the 0149 Antibodies or fragments thereof, disclosed herein composition an agent which delays absorption, for example, can be administered on multiple occasions. Intervals aluminum monostearate and gelatin. between single dosages can be, e.g., daily, weekly, monthly 0145. In any case, sterile injectable solutions can be or yearly. Intervals can also be irregular as indicated by prepared by incorporating an active compound (e.g., an measuring blood levels of polypeptide or target molecule in antibody by itself or in combination with other active the patient. In some methods, dosage is adjusted to achieve agents) in the required amount in an appropriate solvent with a certain plasma antibody or toxin concentration, e.g., one or a combination of ingredients enumerated herein, as 1-1000 ug/ml or 25-300 ug/ml. Alternatively, antibodies, or required, followed by filtered sterilization. Generally, dis fragments thereof, can be administered as a Sustained release persions are prepared by incorporating the active compound formulation, in which case less frequent administration is into a sterile vehicle, which contains a basic dispersion required. Dosage and frequency vary depending on the medium and the required other ingredients from those half-life of the antibody in the patient. In general, humanized enumerated above. In the case of sterile powders for the antibodies show the longest half-life, followed by chimeric preparation of sterile injectable solutions, the methods of antibodies and nonhuman antibodies. In one embodiment, preparation can be vacuum drying and freeze-drying, which the antibodies, or fragments thereof, disclosed herein can be yields a powder of an active ingredient plus any additional administered in unconjugated form. In another embodiment, desired ingredient from a previously sterile-filtered solution the antibodies disclosed herein can be administered multiple thereof. The preparations for injections are processed, filled times in conjugated form. In still another embodiment, the into containers such as ampoules, bags, bottles, Syringes or antibodies, or fragments thereof, disclosed herein can be vials, and sealed under aseptic conditions according to administered in unconjugated form, then in conjugated form, methods known in the art. Further, the preparations may be or vice versa. packaged and sold in the form of a kit Such as those 0150. The dosage and frequency of administration can described in co-pending U.S. Ser. No. 09/259,337 and U.S. vary depending on whether the treatment is prophylactic or Ser. No. 09/259,338 each of which is incorporated herein by therapeutic. In prophylactic applications, compositions con reference. Such articles of manufacture will in an embodi taining the present antibodies or a cocktail thereof are ment have labels or package inserts indicating that the administered to a patient not already in the disease state to associated compositions are useful for treating a subject enhance the patient's resistance. Such an amount is defined Suffering from, or predisposed to autoimmune or neoplastic to be a “prophylactic effective dose.” In this use, the precise disorders. amounts again depend upon the patient’s state of health and US 2017/0210797 A1 Jul. 27, 2017 32 general immunity, but generally range from 0.1 to 25 mg per pharmaceutically effective amount for the in vivo treatment dose, especially 0.5 to 2.5 mg per dose. A relatively low of mammalian disorders. In this regard, it will be appreci dosage is administered at relatively infrequent intervals over ated that the disclosed antibodies, or fragments thereof, will a long period of time. Some patients continue to receive be formulated so as to facilitate administration and promote treatment for the rest of their lives. stability of the active agent. In certain embodiments, phar 0151. In therapeutic applications, a relatively high dosage maceutical compositions in accordance with the present (e.g., from about 1 to 400 mg/kg of antibody per dose, with invention comprise a pharmaceutically acceptable, non dosages of from 5 to 25 mg being more commonly used for toxic, sterile carrier Such as physiological saline, non-toxic radioimmunoconjugates and higher doses for cytotoxin-drug buffers, preservatives and the like. For the purposes of the conjugated molecules) at relatively short intervals is some instant application, a pharmaceutically effective amount of times required until progression of the disease is reduced or an antibody disclosed herein, conjugated or unconjugated to terminated, and, in particular embodiments, until the patient a therapeutic agent, shall be held to mean an amount shows partial or complete amelioration of symptoms of sufficient to achieve effective binding to a target and to disease. Thereafter, the patient can be administered a pro achieve a benefit, e.g., to ameliorate symptoms of a disease phylactic regime. or disorder or to detect a substance or a cell. In the case of 0152. In one embodiment, a subject can be treated with a tumor cells, the polypeptide will in certain embodiments be nucleic acid molecule encoding a polypeptide disclosed capable of interacting with selected immunoreactive anti herein (e.g., in a vector). Doses for nucleic acids encoding gens on neoplastic or immunoreactive cells and provide for polypeptides range from about 10 ng to 1 g, 100 ng to 100 an increase in the death of those cells. Of course, the mg, 1 ug to 10 mg. or 30-300 ug DNA per patient. Doses for pharmaceutical compositions disclosed herein may be infectious viral vectors vary from 10-100, or more, virions administered in single or multiple doses to provide for a per dose. pharmaceutically effective amount of the polypeptide. 0153. Therapeutic agents can be administered by paren 0157. In keeping with the scope of the present disclosure, teral, topical, intravenous, oral, Subcutaneous, intraarterial, the antibodies disclosed herein may be administered to a intracranial, intraperitoneal, intranasal or intramuscular human or other animal in accordance with the aforemen means for prophylactic or therapeutic treatment. Intramus tioned methods of treatment in an amount Sufficient to cular injection or intravenous infusion can be used for produce a therapeutic or prophylactic effect. The polypep administration of an antibody disclosed herein. In some tides disclosed herein can be administered to such human or methods, therapeutic antibodies, or fragments thereof, are other animal in a conventional dosage form prepared by injected directly into the cranium. In some methods, anti combining the antibody disclosed herein with a conventional bodies, or fragments thereof, are administered as a Sustained pharmaceutically acceptable carrier or diluent according to release composition or device, such as a MedipadTM device. known techniques. It will be recognized by one of skill in the 0154 Agents disclosed herein can optionally be admin art that the form and character of the pharmaceutically istered in combination with other agents that are effective in acceptable carrier or diluent is dictated by the amount of treating the disorder or condition in need of treatment (e.g., active ingredient with which it is to be combined, the route prophylactic or therapeutic). Additional agents are those of administration and other well-known variables. Those which are art recognized and are routinely administered for skilled in the art will further appreciate that a cocktail a particular disorder. comprising one or more species of polypeptides according to 0155 While a great deal of clinical experience has been the present invention may prove to be particularly effective. gained with 131I and 90Y, other radiolabels are known in the 0158 Also disclosed herein is a method of treating a art and have been used for similar purposes. Still other condition caused by increased expression of CB1 or radioisotopes are used for imaging. For example, additional increased sensitivity to CB1 comprising administering to a radioisotopes which are compatible with the scope of the patient or other subject orally, parenterally by a solution for instant invention include, but are not limited to, 123I, 125I, injection, by inhalation, or topically a pharmaceutically 32P 57Co., 64Cu, 67Cu, 77Br, 81Rb, 81 Kr, 87Sr., 113In, effective amount of a CB1 antibody. 127Cs, 129Cs, 1321, 197Hg, 203Pb, 206Bi, 177Lu, 186Re, 212Pb, 212Bi, 47Sc, 105Rh, 109Pd, 153Sm, 188Re, 199Au, 0159. Also disclosed herein is the use of a pharmaceuti 225Ac, 21 1A 213Bi. In this respect alpha, gamma and beta cally effective amount of a CB1 antibody for the manufac emitters are all compatible with in the instant invention. ture of a medicament for treating a condition caused by Further, in view of the instant disclosure it is submitted that increased expression of CB1 or increased sensitivity to CB1 one skilled in the art could readily determine which radio comprising administering to a patient or other subject orally, nuclides are compatible with a selected course of treatment parenterally by a solution for injection, by inhalation, or without undue experimentation. To this end, additional topically. radionuclides which have already been used in clinical (0160. In some embodiments, the disclosed isolated anti diagnosis include 125I, 123I, 99Tc, 43K, 52Fe, 67Ga, 68Ga, bodies and antigen binding fragments thereof have the as well as 111 In. Antibodies have also been labeled with a advantage of minimal brain penetration. In some embodi variety of radionuclides for potential use in targeted immu ments, the isolated antibodies and fragments thereof exhibit notherapy (Peirersz et al. Immunol. Cell Biol. 65: 111, high selectivity for CB1 receptor and do not penetrate the 1987). These radionuclides include 188Re and 186Re as blood brain barrier, or exhibit reduced penetration of the well as 199 Au and 67Cu to a lesser extent. U.S. Pat. No. blood brain barrier relative to small molecule CB1 receptor 5,460,785 provides additional data regarding such radioiso compounds, so that CNS side effects are minimized. In topes and is incorporated herein by reference. further embodiments, the isolated antibodies and fragments 0156. As previously discussed, the antibodies, or frag thereof do not penetrate the blood brain barrier, or exhibit ments thereof, disclosed herein can be administered in a reduced penetration of the blood brain barrier relative to US 2017/0210797 A1 Jul. 27, 2017 Small molecule CB1 receptor compounds such as rimona 0172 8. The isolated antibody or antigen binding frag bant, following intravenous injection. ment of embodiment 7, wherein the antibody or fragment 0161 In one embodiment, the antibodies and binding has CB1 receptor signaling inhibiting activity that is at least fragments or variants thereof disclosed herein may be equivalent in potency relative to Small molecule rimonabant, administered to the subject by at least one route selected wherein the potency is measured by inhibition of CB1 from parenteral, Subcutaneous, intramuscular, intravenous, receptor agonist-mediated signal transduction in a cAMP intrarticular, intrabronchial, intraabdominal, intracapsular, assay. intracartilaginous, intracavitary, intracelial, intracerebellar, 0173 9. The isolated antibody or antigen binding frag intracerebroventricular, intracolic, intracervical, intragastric, ment of embodiment 7, wherein the antibody or fragment intrahepatic, intramyocardial, intraosteal, intrapelvic, intra has CB1 receptor signaling inhibiting activity that is at least pericardiac, intraperitoneal, intrapleural, intraprostatic, 3 fold more potent relative to small molecule rimonabant, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspi wherein the potency is measured by inhibition of CB1 nal, intrasynovial, intrathoracic, intratympanic, intrauterine, receptor agonist-mediated signal transduction in a cAMP intravesical, intravitreal, bolus, Subconjunctival, vaginal, assay. rectal, buccal, Sublingual, intranasal, and transdermal. 0.174 10. The isolated antibody or antigen binding frag 0162 The present invention provides isolated antibodies ment of embodiment 7, wherein the antibody or fragment and antigen binding fragments thereof, and nucleic acids has CB1 receptor signaling inhibiting activity that is at least encoding Such antibodies and fragments, as well as compo equivalent in potency relative to Small molecule rimonabant, sitions comprising Such isolated antibodies, fragments, and wherein the potency is measured by the inhibition of CB1 nucleic acids. The present invention further provides phar receptor agonist-mediated ERK phosphorylation. maceutical compositions comprising the isolated antibodies 0.175 11. The isolated antibody or antigen binding frag or fragments thereof, or nucleic acids encoding Such anti ment of embodiment 7, wherein the antibody or fragment bodies or fragments, and further comprising one or more has CB1 receptor signaling inhibiting activity that is at least pharmaceutically acceptable carrier. Pharmaceutically 3 fold more potent relative to small molecule rimonabant, acceptable carriers include, for example, excipients, wherein the potency is measured by the inhibition of CB1 diluents, encapsulating materials, fillers, buffers, or other receptor agonist-mediated ERK phosphorylation. agents. 0176 12. The isolated antibody or antigen binding frag ment of embodiment 1, wherein the antibody or fragment DESCRIPTION OF PARTICULARASPECTS activates or enhances CB1 receptor activity. AND EMBODIMENTS 0177 13. The isolated antibody or antigen binding frag ment of embodiment 1, wherein the antibody or fragment is 0163 The different aspects disclosed herein and their an allosteric modulator of CB1 receptor. embodiments can be combined with each other. In addition, 0.178 14. The isolated antibody or antigen binding frag any of the aspects and their embodiments described above ment of embodiment 1, wherein the antibody or fragment is can be combined with any of the particular aspects and an inverse agonist of CB1 receptor. embodiments described herein below. 0179 15. The isolated antibody or antigen binding frag 0164. Some particular aspects and embodiments that fur ment of embodiment 1, wherein the antibody or fragment is ther serve to illustrate the present invention are provided in murine. the following: 0180 16. The isolated antibody or antigen binding frag 0.165 1. An isolated antibody or antigen binding frag ment of embodiment 1, wherein the antibody or fragment is ment thereof that binds to cannabinoid 1 (CB1) receptor, chimeric. wherein the antibody or fragment has a binding affinity Kd 0181 17. The isolated antibody or antigen binding frag for CB1 receptor of about 1 M or less. ment of embodiment 1, wherein the antibody or fragment is 0166 2. The isolated antibody or antigen binding frag humanized. ment of embodiment 1, wherein the antibody or fragment 0182 18. The isolated antibody or antigen binding frag has a binding affinity Kd for CB1 receptor of about 100 nM ment of embodiment 1, wherein the antibody or fragment or less. selectively binds CB1. 0167 3. The isolated antibody or antigen binding frag 0183) 19. The isolated antibody or antigen binding frag ment of embodiment 1, wherein the antibody or fragment ment of embodiment 1, wherein the antibody is conjugated has a binding affinity Kd for CB1 receptor of about 10 nM to an agent, for example, an additional therapeutic agent, a or less. cytotoxic agent, an immunoadhesion molecule, or an imag 0168 4. The isolated antibody or antigen binding frag ing agent. ment of embodiment 1, wherein the antibody or fragment 0.184 20. The isolated antibody or antigen binding frag has a binding affinity Kd for CB1 receptor of about 1 nM or ment of embodiment 19, wherein the agent is an additional less. therapeutic agent, a cytotoxic agent, an immunoadhesion 0169 5. The isolated antibody or antigen binding frag molecule, or an imaging agent. ment of embodiment 1, wherein the antibody or fragment 0185. 21. The isolated antibody or antigen binding frag binds to an extracellular epitope on CB1 receptor. ment of embodiment 20, wherein the therapeutic agent is 0170 6. The isolated antibody or antigen binding frag rimonabant. ment of embodiment 1, wherein the antibody or fragment 0186 22. The isolated antibody or antigen binding frag binds to human CB1 receptor. ment of embodiment 20, wherein the imaging agent is 0171 7. The isolated antibody or antigen binding frag selected from the group consisting of a radiolabel, an ment of embodiment 1, wherein the antibody or fragment enzyme, a fluorescent label, a luminescent label, a biolumi inhibits CB1 receptor signaling activity. nescent label, a magnetic label, and biotin.