Imgn151-A Next Generation Folate Receptor Alpha Targeting Antibody Drug Conjugate Active Against Tumors With Low, Medium And High Receptor Expression

Folate Receptor alpha (FRα) is an attractive antibody drug conjugate (ADC) target due to its over expression in multiple epithelial malignancies including ovarian, endometrial, triple negative breast, and non-small cell lung cancer, with limited expression on normal tissues. IMGN853 (i.e., mirvetuximab soravtansine and M9346A-sulfo-SPDB-DM4), a FRα targeting ADC, is currently in phase III (MIRASOL) clinical evaluation as monotherapy in patients with platinum-resistant epithelial ovarian cancer with high levels of FRα expression. The MIRASOL study builds on the results from the prior randomized study, FORWARD I, which demonstrated that improved outcomes with IMGN853 correlated with FRα expression, with the strongest treatment effects for all efficacy endpoints in ovarian cancer patients with FRα-high disease (Moore, ESMO 2019). In order to address the unmet needs of additional patient populations, we sought to develop a next generation FRα-targeting ADC active against tumors with a broad range of FRα expression. Development of a new molecular entity with the desired antitumor properties included optimization of the antibody format and the linker-payload. The resulting lead ADC denoted IMGN151 comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to the highly potent maytansinoid derivative DM21 via a stable cleavable peptide linker. The average drug per antibody ratio is 3.5. The binding, internalization and processing of the biparatopic IMGN151 and the parent monospecific antibodies were compared using 3H-antibodies. In tumor cells with medium (JHOS4) and high (KB) FRα expression the biparatopic antibody boosted antibody binding events and processing by 100% and 170%, respectively. The plasma stability of IMGN151 was tested in a cynomolgus monkey pharmacokinetic study. The stable linker increased ADC half-life by 60 hours and conjugate exposure in vivo by 40%, as compared to IMGN853. IMGN151 activity was characterized against cell lines and xenograft models with a wide range of FRα expression and compared to IMGN853. In in vitro studies, both ADCs had similar activity against FRα-high KB cells; IMGN151 was up to 200 times more active against four FRα-medium cell lines. IMGN151 had also notably stronger bystander killing activity in a mixed culture of target-positive and negative cells. In vivo IMGN151 induced complete tumor regressions of human tumor xenograft models with high (KB, H-score of 300), medium (Igrov-1 and Ishikawa, H-score of 140 and 100, respectively) and low (Ov-90, H-score of 30) FRα expression. All tested doses were well tolerated with no body weight loss observed. With a novel biparatopic antibody and linker payload design, IMGN151 has shown potent antitumor activity against ovarian cancer models with a broad range of FRα expression, which warrants further development into the clinic for patients with tumors expressing FRα at a wide range of levels. Citation Format: Olga Ab, Laura M. Bartle, Leanne Lanieri, Jose F. Ponte, Qifeng Qiu, Surina Sikka, Juliet A. Costoplus, Wayne Deats, Nicholas C. Yoder, Wayne C. Widdison, Katherine Mucciarone, Kate Selvitelli, Ying Chen, Neeraj Kohli, Thomas Chittenden, Richard Gregory, Yulius Setiady, Eric H. Westin. IMGN151 - A next generation folate receptor alpha targeting antibody drug conjugate active against tumors with low, medium and high receptor expression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2890.