Abstract 4531: Effects of drug load on therapeutic index for antibody-maytansinoid conjugates

Abstract

Abstract Antibody-drug conjugates (ADCs) are being actively pursued as a new modality to treat cancer following the regulatory approval of Adcetris@ and Kadcyla@. ADCs consist of a cytotoxic agent, or drug, conjugated to a targeting antibody (Ab) through a linker. The two approved ADCs (and most ADCs now in the clinic) are heterogeneous conjugates with an average molar drug to Ab ratio (DAR) of 3-4 (potentially ranging from 0-8 for individual molecules). To understand the effects of different DAR ranges on the preclinical properties of ADCs using a maytansinoid cytotoxic agent, we prepared a series of conjugates with a cleavable linker (M9346A-sulfo-SPDB-DM4 targeting folate receptor alpha) or an uncleavable linker (J2898A-SMCC-DM1 targeting epidermal growth factor receptor) with varying DAR, and evaluated their biochemical characteristics, in vivo stability, efficacy, and tolerability. Both M9346A-sulfo-SPDB-DM4 and J2898A-SMCC-DM1 conjugates with low (average ∼2, range 0-4) to very high DAR (average 10, range 7-14) were prepared in good yield, high monomer content and low free drug levels. At constant Ab concentration, the in vitro potency consistently increased with increasing DAR. We then characterized the in vivo disposition of these ADCs. First, pharmacokinetic analysis showed that conjugates with an average DAR below ∼6 had comparable clearance rates, but at an average DAR around 9-10 rapid clearance was observed. Biodistribution studies in mice showed that these 9-10 DAR conjugates rapidly distribute to the liver, with the maximum%ID/g for this organ at 24-28% compared with 7-10% for lower DAR conjugates (all at 2-6 h post-injection). We further studied the efficacy of these ADCs in mouse xenograft models at both constant antibody and constant maytansinoid doses. At constant Ab dose, conjugates with average DAR ∼6 are more efficacious than conjugates with DAR ∼3. However, DAR 9-10 conjugates are either less or similarly active compared to DAR 6 conjugates, consistent with the observed rapid clearance. At constant maytansinoid dose, conjugates with 2 - 6 DAR show similar efficacy, while those with 9-10 DAR were again less active. Tolerability studies monitoring body weight loss show that conjugates with different DAR, even as high as 9-10, have comparable tolerability based on total administered maytansinoid dose. In summary, our preclinical findings on tolerability and efficacy suggest that maytansinoid conjugates with DAR in the range between 2 - 6 have better therapeutic index than conjugates with very high DAR (∼9-10). These very high DAR ADCs suffer from decreased efficacy likely due to faster clearance. These results support the use of DAR 3-4 for maytansinoid ADCs, but suggest the exploration of lower or higher DAR depending on the biology of the target antigen. Citation Format: Xiuxia Sun, Jose F. Ponte, Nicholas C. Yoder, Jennifer Coccia, Leanne Lanieri, Rassol Laleau, Qifeng Qiu, Rui Wu, Erica Hong, Megan Bogalhas, Lintao Wang, Erin K. Maloney, Olga Ab, Hans K. Erickson, Thomas A. Keating, Ravi Chari, John M. Lambert. Effects of drug load on therapeutic index for antibody-maytansinoid conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4531. doi:10.1158/1538-7445.AM2015-4531