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

Abstract

Purpose: 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). Experimental Design: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. Results: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. 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. Conclusions: 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.

Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma

“…CD24 is a highly expressed, anti-phagocytic signal in several cancers and demonstrates therapeutic potential for CD24 blockade in cancer immunotherapy [68]. ICAM-1 antibodies showed potent anti-myeloma activity in multiple studies [69] [70] [71]. CD44 mediates resistance to lenalidomide in multiple myeloma [72], and CD44-targeted T cells mediate potent anti-tumour effects against multiple myeloma [73].…”

Cancer drug resistance in multiple myeloma

“…Precision medicines as well as biotherapeutic agents, including therapeutic monoclonal antibodies such as the anti-CD38 MoAb Daratumumab and isatuximab, and the anti-signaling lymphocyte activation marker F7, antibody elotuzumab, antibody-drug conjugates, and bispecific antibodies (BiAb) have been developed to damage drug-resistant MM clones as well as alter the immunosuppressive bone marrow microenvironment with some very promising clinical data regarding their clinical impact potential [ 1 , 4 , 39 ] . T-cell redirecting BiAb and bispecific T-cell engagers (BiTES) targeting CD38, the orphan G protein-coupled receptor GPRC5D, and the B-cell maturation antigen (BCMA)/CD269 on MM cells and CD3 antigen on T-cells facilitate the CTL-mediated destruction of drug-resistant MM cells in cytolytic synapses [ 4 , 40 ] .…”

Emerging Role of Antibody-Drug Conjugates and Bispecific Antibodies for the Treatment of Multiple Myeloma

“…Naked anti-ICAM1 antibodies were active in preclinical studies and safe in myeloma patients but showed limited clinical efficacy; thus, an anti-ICAM1 ADC was developed for better targeting MM cells. Potent anti-myeloma cytotoxicity was displayed by anti-ICAM1 ADC in vitro and in vivo [ 69 , 70 ]. In a study conducted by Hansson et al (NCT010252060), BI-505, a human anti-ICAM-1 mAb, was evaluated for safety and tolerability in advanced RRMM patients.…”