ICAM1-Targeted Immunotherapy Is Effective in Multiple Myeloma

Therapeutic antibodies such as the CD20-targeting antibody rituximab target tumor-specific cell surface receptors to stimulate antitumor immune responses. High-throughput functional screening of a human antibody library has characterized additional antitumor antibodies that show specificity for malignant B-cell receptors and induce tumor programmed cell death. This unbiased approach identified antibodies targeting intercellular adhesion molecule 1 (ICAM1), which is overexpressed in multiple myeloma and has previously been implicated in disease progression and chemotherapeutic resistance but not tumor cell death. Veitonmäki and colleagues assessed the therapeutic potential of the human ICAM1 antibody BI-505 and found that it was more effective than rituximab at inhibiting CD20-positive B-cell lymphoma xenograft growth and prolonged survival of tumor-bearing mice. In addition, the BI-505 epitope was highly expressed on primary multiple myeloma cells, and treatment with BI-505 suppressed the growth of ICAM1-expressing multiple myeloma cells in vivo. BI-505 showed enhanced antimyeloma activity, including decreased tumor burden in the bone marrow and protection from myeloma-driven bone remodeling, compared with clinically relevant doses of currently used treatments in 2 experimental mouse models of advanced disseminated multiple myeloma. This antitumor effect was dependent on crosslinking of the antibody Fc domain to Fcγ receptors (FcγR) on the cell surface of tumor-infiltrating macrophages. The Fc–FcγR interaction stimulated macrophage-mediated antibodydependent cell phagocytosis of myeloma cells, and depletion of macrophages but not natural killer cells ablated the in vivo antimyeloma activity of BI-505. Importantly, BI-505 did not trigger apoptosis in normal human ICAM1-positive cells and did not activate T-cell proliferation or induce cytokine release in vitro, suggesting that this antibody may be well tolerated. These findings validate this functional screening approach for antitumor antibody discovery and identify a role for ICAM1 in tumor cell death and as a therapeutic target in multiple myeloma.

Veitonmäki N, Hansson M, Zhan F, Sundberg A, Löfstedt T, Ljungars A, et al. A human ICAM-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo. Cancer Cell 2013;23:502–15.

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