Abstract 2012: A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility

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Abstract Historically, increasing the drug-to-antibody ratio (DAR) in an antibody-drug conjugate (ADC) significantly raises aggregation propensity as a result of the hydrophobicity of the payload. Consequently, DARs are commonly limited to 4, forcing developers to incorporate very high potency payloads to achieve the required efficacy. This, combined with chemical instability and off-target uptake, often results in dose-limiting toxicities and narrow therapeutic indexes. In this study, we used a novel and flexible multivalent linker technology to construct two ADCs targeting HER-2 with the monoclonal antibody, trastuzumab and interchain cysteine bioconjugation. One ADC incorporated monomethyl auristatin E (MMAE) as the drug payload at average DAR 16 whilst the second incorporated the camptothecin analog, SN38, as the drug payload also at average DAR 16. The ADCs were characterized by liquid chromatography-mass spectrometry (LC-MS), size-exclusion chromatography (SEC), hydrophobic interaction chromatography (HIC) and SDS-PAGE and were then tested for efficacy in a range of HER-2 positive cell lines in vitro, and tumor growth inhibition studies using NCI-N87 cells in a mouse xenograft. Both ADCs remained > 95% monomeric (no aggregation) and demonstrated greater chemical stability in ex-vivo serum stability studies compared to comparator ADC constructs utilizing a clinically validated linker and the same payload release chemistry. In in vitro cell killing studies, the ADCs demonstrated target-specific cell killing with the SN38 average DAR 16 ADC achieving a disproportionate 30-fold increase in IC50 (by ADC concentration) compared to a DAR 8 comparator. Dose dependent tumor growth inhibition was observed in an HER-2 positive NCI-N87 mouse xenograft model with no change in mouse body weight, and good systemic exposure. These data demonstrate our capability, using a novel multivalent linker technology, to construct ADCs with DARs considerably greater than DAR 8 which are chemically stable, shield payloads from hydrophobic interactions (no aggregation), demonstrate good in vivo exposure profiles and which are highly efficacious in vitro and in vivo. Higher DARs will permit the incorporation of lower potency and targeted small molecule payloads into ADCs which will result in targeted cancer therapeutics with wider therapeutic indexes through the delivery of greater concentrations of payload to the tumor microenvironment and lower, payload-associated, dose-limiting toxicity. Citation Format: Ludovic Juen, Adam J. Collier, Anthony W. Tolcher, Myriam M. Ouberai. A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2012.