Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma

• Published in: Clinical cancer research Vol. 26; no. 22; pp. 6028 - 6038
• Main Authors: Sherbenou, Daniel W, Su, Yang, Behrens, Christopher R, Aftab, Blake T, Perez de Acha, Olivia, Murnane, Megan, Bearrows, Shelby C, Hann, Byron C, Wolf, Jeffery L, Martin, Thomas G, Liu, Bin
• Format: Journal Article
• Language: English
• Published: United States 15.11.2020
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - immunology; Adult; Aged; Animals; Antibodies, Anti-Idiotypic - immunology; Antibodies, Anti-Idiotypic - pharmacology; Antibodies, Monoclonal - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Flow Cytometry; Heterografts; Humans; Immunoconjugates - immunology; Immunoconjugates - pharmacology; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - immunology; Male; Mice; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - immunology; Multiple Myeloma - pathology
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-0400

New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC). Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines , orthotopic xenografts , and patient samples . The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity and . In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.