Imgc936, An Investigational Adam9-Targeting Antibody Drug Conjugate, Is Active Against Patient-Derived Adam9-Expressing Xenograft Models.

Abstract Background: A disintegrin and metalloprotease (ADAM) 9 is a member of the ADAM family of transmembrane proteins. ADAM9 overexpression correlates with tumor progression, metastasis and poor prognosis in multiple cancers. IMGC936, an ADAM9-targeting antibody drug conjugate (ADC), is comprised of a high-affinity humanized monoclonal antibody site-specifically coupled to DM21 at a drug-antibody ratio of 2.0. DM21 is a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker. IMGC936 is in a phase 1 dose escalation study evaluating safety and pharmacokinetics in cancer patients. The goals of this study were: 1) to explore ADAM9 expression in various solid tumors, and 2) to evaluate the activity of IMGC936 in clinically relevant patient-derived xenograft (PDX) models with ADAM9 expression similar to that observed in human tumors. Methods: ADAM9 expression was evaluated on primary patient and PDX formalin-fixed, paraffin-embedded samples with the anti-ADAM9 antibody D64B5 (Cell Signaling Technology). Expression of ADAM9 was quantitated by H-score to capture the frequency and intensity of staining. Mice bearing PDX tumors were dosed once at 8.6 mg/kg of IMGC936, which delivered 100 µg/kg of DM payload. Anti-tumor activity was defined by NCI standards: median tumor volume of treated mice over control mice (%) > 42% (inactive), ≤ 42% (active), and <10% (highly active). Results and Conclusions: ADAM9 was highly expressed in multiple tumor types. A majority of the tumor samples had medium to high levels of ADAM9 with 62% of non-small cell lung carcinoma (NSCLC), 65% of triple negative breast cancer (TNBC), 73% of gastric cancer, and 85% of pancreatic cancer samples having H- scores of 101 to 300. The remaining tumor samples had lower levels of ADAM9 expression (H-score 1 to 100) with only 1.2% of NSCLC samples being ADAM9-negative. Activity of IMGC936 was analyzed in PDX models derived from NSCLC, TNBC, pancreatic and gastric cancers. The range of ADAM9 expression was 27 to 226 by H-score, with 80% of the samples having H-scores above 101. A single dose of IMGC936 at 8.6 mg/kg was well tolerated. Across the tumor types tested, IMGC936 was active or highly active in 24 out of 35 models (69%) with complete regressions in 6 models (4 NSCLC, 2 TNBC). The 24 IMGC936 sensitive models had H-scores between 65 and 224. The 11 non-sensitive models had H-scores between 27 and 226. The data suggest that factors independent of ADAM9 expression contribute to model sensitivity toward IMGC936 and warrant further biomarker exploration. These studies demonstrate that ADAM9 is highly expressed in a large number of solid tumor indications and show that IMGC936 has activity against multiple solid tumor types with a wide range of clinically relevant ADAM9 levels. These data support the clinical evaluation of IMGC936 (NCT04622774). Citation Format: Olga Ab, Juniper A. Scribner, Kerstin Sinkevicius, Deryk Loo, Stuart W. Hicks, Krystal Watkins, Francine Z. Chen, Christopher Espelin, Marian Themeles, Ying Li, Chet Bohac, Patrick Zweidler McKay, Paul A. Moore, Callum M. Sloss, Ezio Bonvini, Eric H. Westin. IMGC936, an investigational ADAM9-targeting antibody drug conjugate, is active against patient-derived ADAM9-expressing xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1841.