IMGN151 is a next-generation Antibody-drug Conjugate designed to address the unmet needs of cancer patients with tumor types expressing lower levels of folate receptor alpha (FRα).
The investigational drug comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative, DM21, via a cleavable peptide linker with enhanced stability, longer half-life, and increased bystander activity.
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.
In preclinical development, the plasma stability of IMGN151 was tested in a cynomolgus monkey pharmacokinetic study. The study demonstrated that the stable linker increased ADC half-life by 60 hours and conjugate exposure in vivo by 40%, compared to mirvetuximab soravtansine (previously known as IMGN853).[1][2]
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 IMGN151 and mirvetuximab soravtansine had similar activity against FRα-high KB cells. However, IMGN151 was up to 200 times more active against four FRα-medium cell lines. Furthermore, IMGN151 had also notably stronger bystander killing activity in a mixed culture of target-positive and negative cells.[2]
In in vivo studies, 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.[2]
Reference
[1] Moore KN, Martin LP, O’Malley DM, Matulonis UA, Konner JA, Perez RP, Bauer TM, Ruiz-Soto R, Birrer MJ. Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study. J Clin Oncol. 2017 Apr 1;35(10):1112-1118. doi: 10.1200/JCO.2016.69.9538. Epub 2016 Dec 28. PMID: 28029313; PMCID: PMC5559878.
[2] 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. | Abstract
