IMGC936 is a first-in-class ADAM9-targeting antibody-drug conjugate (ADC) being co-developed by Immunogen and MacroGenics. The investigational agent is comprised of a high-affinity humanized antibody with YTE mutation site-specifically conjugated to DM21, a next-generation maytansinoid microtubule-disrupting payload, and combined with a stable peptide linker.
Target
ADAM9 is a cell surface protein that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases, which have been implicated in cytokine and growth factor shedding and cell migration. Dysregulation of ADAM9 has been implicated in tumor progression and metastasis, as well as pathological neovascularization.
Over-expression and dysregulation of ADAM9 has been implicated in tumor progression and metastasis, as well as pathological neovascularization. Furthermore, ADAM9 overexpression also correlates poor prognosis. [1] For example, ADAM9 is over-expressed in multiple solid tumor types (e.g., non-small cell lung cancer, gastric, pancreatic, triple-negative breast, and colorectal) and minimally expressed on normal tissue, making ADAM9 an attractive target for ADC development.
YTE mutation
To maximize the potential for IMGC936 activity, the M252Y/S254T/T256E (YTE) mutation was introduced into the CH2 domain of the antibody to increase in vivo plasma half-life and exposure.
Maytansinoid payload
DM21 is a peptide-cleavable immolative maytansinoid payload that was designed to allow ADCs to efficiently release hydrophobic metabolites better than conjugates utilizing the disulfide linked maytansinoid DM4. DM21 ADCs typically have similar direct in vitro cytotoxicity as DM4 ADCs against antigen positive cells, but have much greater bystander killing activity in assays where antigen positive cells are mixed with antigen negative cells.[3]
Preclinical development
In preclinical studies, IMGC936 showed cytotoxic activity against a broad panel of ADAM9-positive tumor cell lines. Consistent with the in vitro activity, IMGC936 has shown compelling anti-tumor activity in ADAM9-positive xenograft models. Importantly, IMGC936 showed favorable safety and toxicokinetic profiles in a repeat dose toxicology study in cynomolgus monkeys. Furthermore, In vitro studies demonstrated targeted cytotoxicity of IMGC936 across a panel of ADAM9-positve tumor cell lines with activity at least 2 logs greater than a non-targeting conjugate.
Phase I trial
A Phase 1 dose-escalation is underway and initial data anticipated in 2022
Clinical trials
First-in-Human Study of IMGC936 in Patients With Advanced Solid Tumors – NCT04622774
Reference
[1] Ab O, Scribner JA, Sinkevicius K, Loo D, Hicks SW, Watkins K, Chen FC, Espelin C, Themeles M, Li Y, Bohac C, Zweidler-McKay P, Moore PA, Sloss C, Bonvini E, Westin EH IMGC936, an investigational ADAM9-targeting antibody drug conjugate, is active against patient-derived ADAM9-expressing xenograft models. Cancer Res (2021) 81 (13_Supplement): 1841 | Abstract
[2] Hicks SW, Loo D, Sinkevicius K, Scribner JA, Barat B, Yoder NC, Espelin C, Chen FZ, Themeles M, Lucas J, Brown JG, Matin B, Fuller ME, Lee J, Salomon PL, Costoplus J, Yancey S, Diedrich G, Gorlatov S, Son T, Wolff C, Chiechi M, Li P, Spliedt M, Ciccarone V, Hooley J, Gantt N, Tamura J, Donahue KA, Moore PA, Johnson S, Chittenden T, Gregory R, Bonvini E. IMGC936, a first in-class ADAM9-targeting antibody-drug conjugate, demonstrates promising anti-tumor activity. Cancer Res (2019) 79 (13_Supplement): 1533 | Abstract
[3] Deats W, Widdison W, Costoplus J, Matin B, McBrine N, Bartle L, Ab O, Gregory R, Pinkas J. Preclinical evaluation of DM21, a next-generation maytansinoid payload with a stable peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3898. | Abstract
