title: A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy.
abstract: Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Yurkovetskiy
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Mao
authors.initials: M
authors.lastname: Yin
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Natalya
authors.initials: N
authors.lastname: Bodyak
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Cheri A
authors.initials: CA
authors.lastname: Stevenson
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Thomas
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hammond
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: LiuLiang
authors.initials: L
authors.lastname: Qin
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Bangmin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Dmitry R
authors.initials: DR
authors.lastname: Gumerov
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Ter-Ovanesyan
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts.
authors.forename: Alex
authors.initials: A
authors.lastname: Uttard
authors.affiliation: Mersana Therapeutics, Inc., Cambridge, Massachusetts. tlowinger@mersana.com.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Lowinger
mesh_terms: D000080:Acetals / Q000737:chemistry; D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D061986:MCF-7 Cells; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011108:Polymers / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D000069283:Rituximab / Q000737:chemistry / Q000276:immunology; D013997:Time Factors; D000068878:Trastuzumab / Q000737:chemistry / Q000276:immunology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014748:Vinca Alkaloids / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080:Acetals; D018951:Antigens, CD20; D018796:Immunoconjugates; D011108:Polymers; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D000068878:Trastuzumab; D014748:Vinca Alkaloids; C506479:poly(1-hydroxymethylethylene hydroxymethylformal); C016067:polyacetal