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(12) Patent Application Publication (10) Pub. No.: US 2015/0017246 A1 Huang (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2015/0017246 A1 Huang (43) Pub US 2015.0017246A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0017246 A1 Huang (43) Pub. Date: Jan. 15, 2015 (54) NOVEL CROSSLINKING REAGENTS, Publication Classification MACROMOLECULES, THERAPEUTIC BIOCONJUGATES, AND SYNTHETIC (51) Int. Cl. METHODS THEREOF A647/48 (2006.01) CI2N II/06 (2006.01) (71) Applicant: CellMosaic, Inc., Worcester, MA (US) (52) U.S. Cl. CPC ............ A61K 47/4823 (2013.01): CI2N II/06 (72) Inventor: Yumei Huang, Lexington, MA (US) (2013.01); A61K 47/48369 (2013.01); A61 K 47/48238 (2013.01) USPC ....... 424/490; 536/1.11: 435/181: 530/391.9; (73) Assignee: CellMosaic, Inc., Worcester, MA (US) 530/402:536/6.4 (57) ABSTRACT (21) Appl. No.: 14/156.224 The invention provides novel chemical entities based on Sugar alcohols. These new chemical entities are biocompat ible and biodegradable. The molecules can be made in a (22) Filed: Jan. 15, 2014 single and pure form. The molecular weights of these mol ecules range from small (<1000 Da) to large (1000-120,000 Da). The Sugar alcohol-based molecules can have functional Related U.S. Application Data groups throughout the molecule for crosslinking compounds, Continuation-in-part of application No. PCT/US2012/ Such as the preparation of antibody-drug conjugates, or to (63) facilitate the delivery of therapeutic proteins, peptides, 047255, filed on Jul. 18, 2012. siRNA, and chemotherapeutic drugs. Also provided are new (60) Provisional application No. 61/509,296, filed on Jul. conjugate entities prepared through Sugar alcohol molecules. 19, 2011, provisional application No. 61/754,571, Methods of synthesizing Sugar alcohol-based molecules and filed on Jan. 19, 2013. conjugates are also within the scope of the invention. Patent Application Publication Jan. 15, 2015 Sheet 1 of 12 US 201S/001 7246 A1 J?Xu]]©Edeldeu.eduuOO Patent Application Publication Jan. 15, 2015 Sheet 2 of 12 US 201S/001 7246 A1 Patent Application Publication Jan. 15, 2015 Sheet 3 of 12 US 201S/001 7246 A1 Patent Application Publication Jan. 15, 2015 Sheet 4 of 12 US 201S/001 7246 A1 OHC) e,qred Patent Application Publication Jan. 15, 2015 Sheet 5 of 12 US 201S/001 7246 A1 Patent Application Publication Jan. 15, 2015 Sheet 6 of 12 US 201S/001 7246 A1 Z5),HC) Patent Application Publication Jan. 15, 2015 Sheet 7 of 12 US 201S/001 7246 A1 HÕ Patent Application Publication Jan. 15, 2015 Sheet 8 of 12 US 201S/001 7246 A1 Patent Application Publication Jan. 15, 2015 Sheet 9 of 12 US 201S/001 7246 A1 (C)HO Patent Application Publication Jan. 15, 2015 Sheet 10 of 12 US 201S/001 7246 A1 VýSUU » ---- Patent Application Publication US 201S/001 7246 A1 Patent Application Publication Jan. 15, 2015 Sheet 12 of 12 US 201S/001 7246 A1 US 2015/001 7246 A1 Jan. 15, 2015 NOVEL CROSSLINKING REAGENTS, 0006 wherein MACROMOLECULES, THERAPEUTIC 0007 each M is independently selected from the group BIOCONJUGATES, AND SYNTHETIC consisting of a protein, an enzyme, an antibody, an antibody METHODS THEREOF fragment, a polypeptide, an oligonucleotide, an oligonucle otide analog, a polysaccharide; FIELD OF THE INVENTION 0008 each B is a single MW modified sugar alcohol poly mer, comprising: 0001. The invention relates to novel sugar alcohol-based 0009 from 2 to about 2000 sugar alcohol monomer(s): crosslinking reagents, macromolecules, therapeutic conju 0010 wherein each monomer has from 3 to about 14 gates, and synthetic methods. More specifically, the invention —OR' groups; relates to novel chemical entities that may be used for label I0011 wherein R' is independently selected from ing, conjugation, modification, molecule immobilization, the group consisting of hydrogen, C-C alkyl, ben therapeutic or diagnostic agents, and in drug delivery. Fur Zoyl, acetyl, benzyl, C-C alkylsilyl cyclic ortho thermore, the invention relates to novel conjugates prepared ester, actinide, acetate, tetrahydropyranyl, tetrahy through new Sugar alcohol-based crosslinking reagents and drofuranyl, and tetrahydrothiofurany; macromolecules. 0012 each L is independently selected from the group consisting of: BACKGROUND (0013 a Rand, a structure of V. R V , wherein: 0002 Bioconjugation technologies have been adapted in 0014 V and V are independently selected from the the biotechnology and pharmaceutical industries for the group consisting of: preparation of drug entities, detection reagents, and formula 00.15 Diels-Alder adduct, a 1,3-dipolar tion strategies (Greg T. Hermanson “Bioconjugate Tech (0016 adduct, —C(=G)-G-, -G-C(=G)-, -G-, niques”, 2008, Elsevier Inc.; Christof M. Niemeyer “Biocon G'-C(=G)-G'-, - S S -, - S -(CH2), S(O) jugation Protocols: Strategies and Methods”, 2004, Humana 2 . —S(O) -(CH2), S -, -S(O), N(R)—, Press, Inc.). Bioconjugation is a chemical process that links N(R) S(O) , C(O) NH NH-CH , together two or more biomolecules, including conjugation, C(O) NH N=CH , CH N. NH C labeling, modification, or immobilization of the biomol ecules. SUMMARY OF THE INVENTION 0003. The present invention provides a novel class of mol ecules based on Sugar alcohol (SA), their applications in conjugate preparation, and methods for synthesizing these SA-based molecules. The invention is based, in part, on SAS with better hydrophilicity and higher hydrodynamic volume than polyethyleneglycol (PEG). The invention is also based, in part, on SAS that can be derivatized and modified to allow for the incorporation of various functional groups and activa tion groups to produce SA crosslinking reagents. The inven tion is also based, in part, on SAS that can be further reacted with various other SAS to prepare single and pure high molecular weight (MW) compounds (SA macromolecules), including, for example, linear SA macromolecules and 3/ Sophisticated two- or three-dimensional architectures, such as branched, cyclic, and hyperbranched SA macromolecules. 0004. The advantages of SA macromolecule compounds of the invention compared to existing compounds include, for example, (i) super hydrophilicity conferred from SAS that can be used to modulate biomolecule properties after conjuga h's tion; (ii) the ability to make crosslinking reagents with ver satile functional groups; (iii) the availability of single and pure higher MW compounds; (iv) multivalent conjugation sites allowing higher loading of drug molecules; (V) an improved hydrodynamic radius; (vi) biodegradablity and bio , the compatibility; and (vii) natural, inexpensive starting materi als. 0017 wherein: 0005. In one aspect, the invention generally relates to a 0018 each G' is independently selected from NR, O, conjugate having a chemical structure selected from the and S; group consisting of 0.019 each G' is independently O or S: I0020 each G is independently selected from S, O, M-(L-B). Formula (I), and NR, and SO; B-(L-M), Formula (II) 0021 each G' is independently O or NR; US 2015/001 7246 A1 Jan. 15, 2015 (0022 each R is independently selected from a bond, -continued C-C alkyl, -(CH2CH2O)o , —(CH2CH2O). 10—CH2—, optionally Substituted alicyclyl, heteroali cyclyl, aryl, a peptide, and a peptidomimetic oligomer, I0023 each Risindependently selected from hydrogen, C-Cs alkyl, —(OCH2CH2), optionally substituted alicyclyl, and optionally substituted heteroalicyclyl; (0024) each R is independently C-Cs alkyl: he 0025 u is an integer from 1 to about 20; and, 0026. In another aspect, the invention generally relates to a conjugate A conjugate having chemical structural Formula (III): , the (M2-L)-B (III) 0027 wherein 0037 wherein: 0028 each M is independently selected from the group 0038 each G' is independently selected from NR, O, consisting of a metabolite, a fluorescent compound, a chemi and S; luminescent compound, a mass tag, a chromophore, biotin, a 0.039 each G' is independently O or S: toxin, a drug, a chemotherapeutic agent, a cytotoxic agent, an I0040 each G is independently selected from S, O, immunosuppressive agent, a diagnostic agent, a radioligand. NR, and SO: and a small molecule, 0041 each G' is independently O or NR; 0029 each B is a single MW modified sugar alcohol poly 0042 each R is independently selected from a bond, mer, comprising: C-C alkyl, -(CH2CH2O)o , —(CH2CH2O). 0.030 from 2 to about 2000 sugar alcohol monomer(s): lo—CH2—, optionally substituted alicyclyl, heteroali 0031 wherein each monomer has from 3 to about 14 cyclyl, aryl, a peptide, and a peptidomimetic oligomer; —OR' groups; I0043) each Risindependently selected from hydrogen, I0032 wherein R is independently selected from C-C alkyl, —(OCHCH), optionally substituted the group consisting of hydrogen, C-C alkyl, ben alicyclyl, and optionally substituted heteroalicyclyl; Zoyl, acetyl, benzyl, C-C alkylsilyl cyclic ortho 0044) each R is independently C-Cs alkyl; ester, actinide, acetate, tetrahydropyranyl, tetrahy 0.045 q is an integer from 1 to about 100. drofuranyl, and tetrahydrothiofurany; 0046. In yet another aspect, the invention generally relates 0033 each L is independently selected from the group a conjugate having a chemical structure selected from the consisting of: group consisting of: 0034) a Rand, a structure of V. R V , wherein: (M1)-L-(B-(L-M2)), (IV) and 0035 V and V are independently selected from the group consisting of: (M-L)-(B-(L-M2)), (V) and 0036 Diels-Alder adduct, a 1,3-dipolar adduct, M1-(L-B-(L-M-2)), (VI) —C(=G)-G-, -G-C(=G')-, -G-, -G-C(=G')-G-, 0047 wherein 0048 each M is independently selected from the group consisting of a protein, an enzyme, an antibody, an antibody fragment, a polypeptide, avidin, Streptavidin, an oligonucle otide, an oligonucleotide analog, a polysaccharide; 0049 each M is independently selected from the group consisting of a metabolite, a fluorescent compound, a chemi luminescent compound, a mass tag, a chromophore, biotin, a toxin, a drug, a chemotherapeutic agent, a cytotoxic agent, an immunosuppressive agent, a diagnostic agent, a radioligand.
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