Abstract 4633: Polyacetal-based immunoconjugates: Next-generation ADCs with high drug loading, alternative payloads, and alternative protein recognition scaffolds (2012)

Abstract 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