Charles E. Hammond

A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy

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.

Abstract 4633: Polyacetal-based immunoconjugates: Next-generation ADCs with high drug loading, alternative payloads, and alternative protein recognition scaffolds

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Antibody drug conjugates (ADCs) are rapidly establishing themselves as an important class of chemotherapeutic agents, with impressive therapeutic potential both in hematological malignancies and in solid tumors, as evidenced by SGN-035 and T-DM1. Despite these impressive results, limitations in the current technologies remain. Current ADCs are typically limited to the use of full-size mAbs, providing excellent target recognition and pharmacokinetics (PK), but tolerating the conjugation of only 3-4 payload molecules. This limitation in payload capacity necessitates the use of extremely toxic drugs such as the auristatins and maytansinoids to maximize the therapeutic effect while maintaining the drug load at a low stoichiometric ratio. The vast majority of less potent but often more specific agents with proven anti-cancer activity are largely excluded from incorporation in ADCs. Similarly, a diversity of smaller (alternative) protein recognition scaffolds, such as scFvs, Fabs, diabodies, minibodies etc. are not readily utilized for ADCs (because of their smaller size, they are often associated with poor PK, and even lower capacity for direct drug conjugation. We wish to report our results with a novel, biodegradable-polymer based conjugation system, which provides several advantages for next-generation ADCs, including: 1) significant drug loading of diverse classes of anti-cancer agents; 2) excellent physicochemical and PK properties; and 3) flexibility for use with full-sized mAbs as well as mAb alternatives such as Fabs. The basis of this new conjugation system is a hydrophilic, fully biodegradable polyacetal carrier (PHF or poly(1-hydroxymethylethylene hydroxymethylformal)) covalently linked via separate, optimized linkers to a targeting moiety (mAb or alternative) and 10-40 molecules of drug payload. The optimized stability of the linker employed for conjugation of the polymer-drug conjugate to the targeting molecule ensures stability in the circulation, while the enzymatically cleavable linker utilized for drug-polymer conjugation provides a controllable, predictable pattern of intracellular drug release. Employing well characterized mAbs and mAb Fab fragments in combination with diverse cytotoxic agents as well as kinase inhibitors, we have demonstrated that this new ADC conjugation system provides several potential advantages over existing approaches. For example, trastuzumab was efficiently conjugated to a PHF-vinca polymer conjugate, with a ratio of 16-20 small molecules per antibody. Clear evidence of in vivo activity was demonstrated in multiple xenograft models. Pharmacokinetic and tissue disposition studies conducted in these models confirmed extended plasma ADC exposure (T1/2 of 3-4 days) and significant drug intratumoral accumulation, correlating well with the high ADC efficacy observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4633. doi:1538-7445.AM2012-4633