Modakafusp Alfa Boosts Anti-Myeloma Activity via CD38 Targeting and IFNα-Driven Immune Activation

1 Modakafusp alfa induced broad immune activation in patients with relapsed/refractory multiple myeloma in a first-in-human clinical trial. 2 Modakafusp alfa boosts anti-tumor activity of bispecific T-cell engagers and conventional monoclonal antibodies in preclinical models. Modakafusp alfa (MODA) is a first-in-class immunocytokine comprising a CD38-targeting IgG4 antibody armed with an attenuated interferon alpha payload. Designed to selectively drive interferon alpha signaling in CD38-positive cells, MODA has the potential to combine direct anti-proliferative effects against CD38-positive tumor cells with stimulation of anti-tumor immunity. Indeed, recent results from the phase 1/2 iinnovate-1 trial (NCT03215030) evaluating MODA monotherapy in relapsed/refractory multiple myeloma (MM) patients demonstrated promising clinical efficacy and manageable toxicity, with signs of immune activation. Here, we performed an in-depth investigation on the targeted immunomodulatory activity of MODA on key CD38-positive immune cell subsets, including T-cells, NK-cells, and monocytes. Mass cytometry-based immune profiling in peripheral blood from iinnovate-1 revealed rapid upregulation of various activation markers across these immune subsets following MODA treatment. Functional in vitro assays with healthy donor immune cells further highlighted MODA’s ability to stimulate adaptive and innate immune effector functions. Notably, MODA boosted T-cell-mediated tumor cell killing when redirected by T-cell engaging bispecific antibody blinatumomab, enhanced NK-cell degranulation or direct cytotoxicity, and potentiated antibody-dependent cellular cytotoxicity mediated by the NK-cell redirecting antibodies daratumumab or elotuzumab. MODA furthermore enhanced the capacity of monocyte-derived macrophages to present antigens to T-cells, suggesting broader immunomodulatory effects beyond direct cytotoxicity. Collectively, these findings establish MODA as a potent immune activator, supporting its exploration in combination with other anti-MM immunotherapies such as conventional monoclonal antibodies or T-cell redirecting therapies.