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 hydroxymethylformal (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. Cancer Res; 75(16); 3365-72. Ó2015 AACR.

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

“…93 The resulting higher drug load per mAb achieved higher IC50 potency. 93 Other approaches to overcome limitations due to low capacity of the colloidal suspensions are the incorporation of hydrophilic stealth polymers carrying drug-linker platforms, 91,92,94 which can enable DARs of 10-20 or to mask hydrophobicity by adding a polymer branch such as PEG 70 or polysarcosine to the linker. 90 These approaches have been shown to reduce net hydrophobicity on HIC and to enable in vivo serum half-life extension.…”

Highly Potent, Anthracycline-based Antibody–Drug Conjugates Generated by Enzymatic, Site-specific Conjugation

“…To circumvent this problem, high DAR ADCs were developed, for example, by using so-called hydrophilic fleximers for attachment of the payloads to the mAb. Because of the highly hydrophilic nature of fleximers, ADCs with a DAR of 20 can be prepared that still exhibit favorable pharmacokinetic properties and substantially improved efficacy (27). Another approach reported recently is based on induction of receptor clustering by targeting two independent epitopes on a TSA.…”

Development of a facile antibody–drug conjugate platform for increased stability and homogeneity

“…For instance, the Fleximer technology conjugates up to 20 drug molecules per antibody without concerns due to the presence of a very hydrophilic polymer. 38 With the Pt( ii ) linker, as it is possible to achieve a maximum DAR of 8, we included a PEG chain in our linker-design to compensate for the drug's hydrophobicity, which decreased aggregation of the resulting ADCs. If more hydrophobic drugs were to be employed or higher DARs were desired, higher chain length of PEG could be built-in to the design.…”