Preclinical data for ImmunoGen’s next-generation anti-folate receptor alpha (FRα) ADC, IMGN151, which is being investigated in tumors with a broad range of FRα expression will be shared in a poster presentation during the 111th Annual Meeting II of the American Association for Cancer Research (AACR), held online, June 22 – 24, 2020.

“Engineered to include multiple antibody and linker-payload innovations, IMGN151 targets tumors with a broad range of FRα expression,” explained Eric Westin, M,D., Vice President of Clinical Development and Translational Sciences at ImmunoGen.

“IMGN151 demonstrated enhanced anti-tumor activity in both in vitro and in vivo preclinical models, with complete regression of human tumor xenograft models induced in those with high, medium, and low levels of FRα expression. Based on these data, we look forward to exploring IMGN151 in the clinic in multiple FRα-positive epithelial malignancies, including ovarian, endometrial, triple-negative breast, and non-small cell lung cancer,” Westin added.

A novel ADC
IMGN151 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 average drug per antibody ratio (DAR) is 3.5.

Advertisement #3
 

In preclinical development, the scientists compared the binding, internalization, and processing of the biparatopic IMGN151 and the parent monospecific antibodies using 3H-antibodies. They observed that in tumor cells with medium and high FRα expression the biparatopic antibody boosted antibody binding events and processing by 100% and 170%, respectively.

Furthermore, 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 (i.e. mirvetuximab soravtansine and M9346A-sulfo-SPDB-DM4), an FRα targeting ADC, is currently in phase III clinical evaluation as monotherapy in patients with platinum-resistant epithelial ovarian cancer with high levels of FRα expression (MIRASOL study).

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

In vitro studies
IMGN151 activity was characterized against cell lines and xenograft models with a wide range of FRα expression and compared to mirvetuximab soravtansine. Cell lines and xenograft models originated from ovarian, endometrial, breast, and cervical cancer.

In in vitro studies, 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 and had a notably stronger bystander killing activity in a mixed culture of target-positive and negative cells. In vivo IMGN151 also 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 bodyweight loss observed.

According to the scientists, with this novel biparatopic antibody and linker payload design IMGN151 has shown potent antitumor activity against ovarian cancer models with a broad range of FRα expression.  Based on these observations, they concluded that further development into the clinic for patients with tumors expressing FRα at a wide range of levels is warranted.

Summary of key findings:

  • The protease-cleavable linker deployed in IMGN151 improves stability and ADC exposure; as compared to IMGN853, pharmacokinetic studies in cynomolgus monkeys showed increased ADC half-life by 60 hours and conjugate exposure in vivo by 40%.
  • The IMGN151 biparatopic format boosted antibody binding events and DM21 payload delivery in tumor cell lines; the increased payload delivery and greater membrane permeability of DM21 enhanced bystander killing activity.
  • In vitro, IMGN151 was more active against FRα-positive cell lines, with the most pronounced effect in cells with low to medium levels of FRα.
  • In vivo, IMGN151 demonstrated better activity over IMGN853 against low and medium levels of FRα, and equivalent activity to IMGN853 against FRα high tumors with lower effective dose; all tested doses were well tolerated.

Clinical trials
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Women With Folate Receptor (FR) Alpha Positive Advanced Epithelial Ovarian Cancer (EOC), Primary Peritoneal or Fallopian Tube Cancer (FORWARD I) – NCT02631876
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (MIRASOL) – NCT04209855

Reference
[1] Ab O, Bartle LM, Lanieri L, Ponte JF, Qiu Q, Sikka S, Costoplus JA, Deats W, Yoder NC, et al. IMGN151 – A next-generation folate receptor-alpha targeting antibody-drug conjugate active against tumors with low, medium, and high receptor expression. AACR 2020 | Virtual Meeting II: E-Posters. Abstract 2890