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(12) Patent Application Publication (10) Pub. No.: US 2016/0280795 A1 Wang (43) Pub US 20160280795A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0280795 A1 Wang (43) Pub. Date: Sep. 29, 2016 (54) BISPECIFIC ANTIBODY WITH TWO (52) U.S. Cl. SINGLE-DOMAIN ANTIGEN-BINDING CPC ......... C07K 16/3007 (2013.01); C07K 16/283 FRAGMENTS (2013.01); C07K 16/2809 (2013.01); C07K (71) Applicant: Zhong Wang, Foster City, CA (US) 16/40 (2013.01); C07K 23.17/35 (2013.01); C07K 23.17/31 (2013.01); C07K 2317/524 (72) Inventor: Zhong Wang, Foster City, CA (US) (2013.01); C07K 2317/526 (2013.01); C07K (21) Appl. No.: 15/178,169 2317/569 (2013.01); C07K 2317/76 (2013.01) y x- - - 9 (22) Filed: Jun. 9, 2016 (57) ABSTRACT Related U.S. Application Data (63) Continuation of application No. PCT/US2014, Provided are bivalent bispecific antibody comprising a first 070985, filed on Dec. 17, 2014. polypeptide comprising a first Fc fragment and a first (60) Provisional application No. 61/918,383, filed on Dec. single-domain antigen-binding (VHH) fragment and a sec 19, 2013. ond polypeptide comprising a second Fc fragment and a Publication Classification second single-domain antigen-binding (VHH) fragment, wherein the first VHH fragment has specificity to a tumor (51) Int. Cl. cell or a microorganism and the second VHH fragment has C T 2% 3.08: specificity to an immune cell, and wherein the first fragment C07K 6/28 (2006.01) is N-terminal to the second fragment. Patent Application Publication Sep. 29, 2016 Sheet 1 of 10 US 2016/0280795 A1 Patent Application Publication Sep. 29, 2016 Sheet 3 of 10 US 2016/0280795 A1 SEQ ID Aligned Sequences No. ER4 -- 1. 2 O 2 7 23. ss 9 WP- - - - - - - - - - - O2 WGOGTOVTVSS-- 23 WGPGTWTWSSGR 28 8 WGKGTOVTVSS-- 2. FIG. 2 (Cont'd) Patent Application Publication Sep. 29, 2016 Sheet 4 of 10 US 2016/0280795 A1 FIG. 3 Patent Application Publication Sep. 29, 2016 Sheet 5 of 10 US 2016/0280795 A1 Anti-His wester Anti-Flag western Detect anti-CEA Detect Anti-CD6 FIG. 4 Patent Application Publication Sep. 29, 2016 Sheet 6 of 10 US 2016/0280795 A1 ->anti-his tag -> anti-flag tag FIG. 5 Patent Application Publication Sep. 29, 2016 Sheet 7 of 10 US 2016/0280795 A1 s' WB v. is. Sisticose treatient M(išax MgCl2: *FB; as fiew after binding: ww2: :orax iris, Siavi Natipi 7.3: i:i-i?: 2 in eitation of {}, \t Glycine pi;3.7 with {{}ai Xi ris. FIG. 6 w wixie kis: S:stics sysk treatises: & ( iš:x: > iFB: Fas low after binding: wi.w3; taxi ris, 50axi NaCl pi 7.5; i:i-E7: 2 in eities of 0. M Gisciae pi i2.7 witi 200a M ris. FIG. 7 Patent Application Publication Sep. 29, 2016 Sheet 8 of 10 US 2016/0280795 A1 W: wei: ces:S sacrisk six: xii. Six vigi: it: Fast low after hiding: wi.: taxi ris, Stax NaCl pi;7.3: 7.2 eation of (). v. Glycine pii 2, with 20 a visis FIG. 8 Patent Application Publication Sep. 29, 2016 Sheet 9 of 10 US 2016/0280795 A1 a --------------------------------------------------------------------------------------------------------- 120 :- 3. 88 fumor ces of ly S$ aw : Eumor ce: NK ce. s 3O Sa & fumor ce-NK cell Bispecific 60 C : x fumor ce--NK ce: Monospecific 2 a. anti-CEA s fumor ce?--NK cel-Monospecific & 20 anti-C) O . SKOW3 29 (CEA negative) (CEA positive) 60 --------------------------------------------------------------------------------------------------------- 140 - 20 SS : : unor cells Way : s :- &Tusmor cells + ce's s 3umor cells +8specifictug/n}} 8 8; unor--ceils-Bispecific (ig/in) 68 3: Tuforces +8i specific{Cugn) 2 & Tumor-- cets--Bispecific Qug/mi) Ae al 20 O SKOW3 -29 (CEA negative) (CEA positive) FIG. 10 Patent Application Publication Sep. 29, 2016 Sheet 10 of 10 US 2016/0280795 A1 140 ; 120 : Tunior ceils orily OO . : Trnor & NK ce: 80 & Tutor re-K ce+Bispecific SO xi or ce-NK 40 ce:+Morospecificanti-Her2 incr ce+NK O - ce3+Morospecific anti-CD16 MD-WAB231 SK-BR (Her2 negative) Her2 positive) FIG. 11 : morces &timor cells + ces 3 Eurmor ceils +Bispecific(3.ug/mi) & Rumor cells-Bispecific lug/mi) 3: Tumor cells +Bispecific Oug/n}} Šumor + cells--Bispecific {10ug/ml) VO-MAB231 SK-BR Her2 negative) (Her2 positive) FIG. 12 US 2016/0280795 A1 Sep. 29, 2016 BSPECIFIC ANTIBODY WITH TWO polypeptide comprising a first Fc fragment and a first SINGLE-DOMAN ANTIGEN-BINDING single-domain antigen-binding (VHH) fragment and (b) a FRAGMENTS second polypeptide comprising a second Fc fragment and a second single-domain antigen-binding (VHH) fragment, CROSS REFERENCE TO RELATED wherein the first VHH fragment has specificity to a tumor APPLICATIONS cell or a microorganism and the second VHH fragment has 0001. This application is a continuation of International specificity to an immune cell. Application No. PCT/US2014/070985, filed Dec. 17, 2014, 0008. In some aspects, the first VHH fragment has speci which claims the benefit under 35 U.S.C. S 119(e) of U.S. ficity to a tumor antigen. In some aspects, the tumor antigen Provisional Application No. 61/918,383 filed on Dec. 19, is selected from the group consisting of CEA, EGFR. Her2. 2013, which is hereby incorporated by reference in its EpCAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, entirety. gpA33, Mucins, TAG-72, CIX, PSMA, folate-binding pro tein, GD2, GD3, GM2, VEGF, VEGFR, Integrin, CVB3, BACKGROUND c5|B1, ERBB2, ERBB3, MET, IGFIR, EPHA3, TRAILR1, TRAILR2, RANKL, FAP and Tenascin. In some aspects, the 0002 Bispecific antibodies (BSMAb, BSAb) are artificial tumor antigen is CEA. proteins composed of fragments of two different monoclonal 0009. In some aspects, the first VHH fragment comprises antibodies and consequently binds to two different types of the amino acid sequence of SEQID NO:1, or an amino acid antigens. In cancer immunotherapy, for instance, BSMAbs having at least about 95% sequence identity thereto. are engineered that simultaneously bind to a cytotoxic cell 0010. In some aspects, the first VHH fragment has speci and a target like a tumor cell to be destroyed. ficity to a virus or a bacterium. In some aspects, the first 0003. At least three types of bispecific antibodies have VHH fragment has specificity to an endotoxin. been proposed or tested, including trifunctional antibody, 0011. In some aspects, the second VHH fragment has chemically linked Fab and bi-specific T-cell engager. In specificity to an antigen selected from the group consisting order to overcome manufacturing difficulties, a first-genera of CD3, CD16, CD19, CD28 and CD64. In some aspects, tion BSMAb, called trifunctional antibody, has been devel the antigen is CD16. oped. It consists of two heavy and two light chains, one each 0012. In some aspects, the second VHH fragment com from two different antibodies. The two Fab regions are prises the amino acid sequence of one of SEQ ID NO:2-5, directed against two antigens. The Fc region is made up from or an amino acid having at least about 95% sequence identity the two heavy chains and forms the third binding site; hence thereto. the name. 0013. In some aspects, the first VHH fragment and/or the 0004. Other types of bispecific antibodies have been second VHH fragment does not contain Val, Gly, Leu, and designed to overcome certain problems, such as short half Trp residues at Kabat positions 37, 44, 45, and 47, respec life, immunogenicity and side-effects caused by cytokine tively. liberation. They include chemically linked Fabs, consisting 0014. In some aspects, each of the Fc fragments com only of the Fab regions, and various types of bivalent and prises a CH2 domain and a CH3 domain. trivalent single-chain variable fragments (scFVs), fusion 0015. In some aspects, the two polypeptides are con proteins mimicking the variable domains of two antibodies. nected with two disulfide bonds. In some aspects, the The furthest developed of these newer formats are the disulfide bonds are connected between cysteine residues bi-specific T-cell engagers (BiTEs) and trifunctional anti located at a hinge region between each of the VHH fragment bodies. and the Fc fragment. 0005. Despite these advancements, there are still major 0016. In some aspects, the Fc fragments comprise one or challenges with bispecific antibodies, such as improving more Substitutions, as compared to a wild-type Fc fragment, manufacturing efficiency, retaining immunogenicity and that form an ionic bond between the Fc fragments. maintaining half-life. 0017. In some aspects, the Fc fragments comprises one or more Substitutions, as compared to a wild-type Fc frag SUMMARY ments, that form a knob-into-the-hole conformational pair 0006. The present disclosure provides a bispecific anti ing between the heavy chain and the Fc fragment. body that includes immunoglobulin Fc fragments connected 0018. Also provided, in one embodiment, is a polynucle to two single-domain antigen-binding fragments (or otide comprising a nucleic acid sequence encoding an anti domains), each of which targets a different antigen. Such a body of any preceding claim. In some aspects, provided is a bispecific antibody, without light chains and with its reduced host cell comprising the polynucleotide of the present dis molecule weight as compared to a conventional antibody, closure. In some aspects, the host cell is a bacterial cell or presents a significant advantage in antibody production and yeast cell. In some aspects, the host cell is E. coli. purification. Unexpectedly, Such a bispecific antibody can 0019. Yet in another embodiment, provided is a method still bind to both antigens effectively, carrying out its of treating a tumor in a patient, comprising administering to intended biological functions.
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