Abstract 4628: Anti-tumor activity and pharmacokinetics of the anti-FOLR1-maytansinoid conjugate IMGN853 is maintained over a wide range of maytansinoid-to-antibody ratios
Authors: Whiteman Kathleen R. , Johnson Holly A. , Sun Xiuxia , Mastico Robert , Emrich Susan , Clancy Lauren , Erickson Hans , Pinkas Jan 
Published: August 2012

Abstract
IMGN853 (M9346A-sulfo-SPDB-DM4) is an antibody-maytansinoid conjugate consisting of the cytotoxic maytansinoid, DM4, covalently linked to the humanized monoclonal antibody M9346A, which selectively binds to folate receptor 1 (FOLR1). Trastuzumab emtansine and other antibody-maytansinoid conjugates that have demonstrated favorable activity and safety in the clinic have maytansinoid-to-antibody ratios (MAR) around 3.5. We assessed the impact of varying MAR on conjugate activity and pharmacokinetics, to determine whether a similar maytansinoid load is optimal for IMGN853. Conjugates of M9346A were prepared with maytansinoid (DM4) loads per antibody ranging from 1.4 to 5.7. All conjugates had high (&gt;90%) monomer content, low (&lt;0.1 %) levels of free maytansinoid, and normal distribution profiles by LC/MS. Conjugates spanning the range of MARs demonstrated comparable binding to FOLR1-expressing cells as assessed by flow cytometry and had comparable in vitro cytotoxicity (based on DM4 concentration) against antigen-positive cells. The plasma pharmacokinetics of M9346A-sulfo-SPDB-[3H]DM4 conjugates with low (2.0), intermediate (3.6) and high (5.1) MAR levels were evaluated in CD-1 mice. There was no impact of varying maytansinoid load, and all conjugates had comparable pharmacokinetic parameters, with plasma circulation half-life of about 5.5 days compared with about 12 days for M9346A. The anti-tumor activity of conjugates with MARs from 1.4 to 5.7 was assessed in two FOLR1-positive xenograft models (KB cervical carcinoma and IGROV-1 ovarian cancer) in SCID mice. Mice bearing established subcutaneous KB or IGROV-1 xenografts were treated at doses known to be active without causing complete tumor regressions (25 or 50 µg/kg based on DM4 concentration, respectively) to allow detection of slight changes in activity based on MAR. Interestingly, conjugates with low MAR were found to have a therapeutic advantage over the higher MAR conjugates in the high FOLR1-expressing KB model, with strong activity of conjugates from 1.4 to 4.7 MAR and a slight reduction in activity observed with the highest MAR conjugates. Conjugate activity across the range of MAR was similar in IGROV-1 tumor-bearing mice. High-quality conjugates over a broad range of maytansinoid loads can be made with the sulfo-SPDB-DM4 linker format, with indistinguishable in vitro activities and without affecting pharmacokinetic properties. The activity of conjugates across a broad MAR range was comparable and not highly dependent on maytansinoid load in high FOLR1-expressing xenograft models. These results, along with the favorable safety and efficacy associated with antibody-maytansinoid conjugates currently under clinical evaluation, led to the selection of a MAR of 3.5 for IMGN853.
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 4628. doi:1538-7445.AM2012-4628