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Modakafusp alfa is a first-in-class antibody–cytokine fusion protein (immunocytokine) consisting of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody (mAb).1 The INF-α fusion protein exhibits a 10,000-fold greater specificity for CD38+ cells versus CD38− when compared with native INF-α.2
Modakafusp alfa, previously known as TAK-573, selectively binds to a unique epitope on CD38, different to the binding epitope of the anti-CD38 mAbs approved for the treatment of multiple myeloma (MM), i.e., daratumumab and isatuximab.1,2 Through the INF-α receptor, modakafusp alfa directs anti-proliferative/apoptotic signals to tumor cells, inducing tumor cell death.2 Besides the anti-myeloma activity, modakafusp alfa also activates innate and adaptive immune cells.2 It is hypothesized that the activated immune cells and dead myeloma cells can produce a synergistic effect in destroying more malignant plasma cells in the bone marrow (Figure 1).2 Furthermore, the specificity of targeting interferon directly to the myeloma cells reduces the potential risk for off-target binding and toxicity in patients with relapsed/refractory multiple myeloma (RRMM).1
Figure 1. Proposed mechanism of action*
NK, natural killer.
*Adapted from Vogel.2
Preliminary results from the ongoing first-in-human, phase I trial of modakafusp alfa in patients with RRMM show clinical activity in response to single-agent therapy with doses starting at 0.1 mg/kg weekly.1
At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Dan Vogl presented updated interim results of the first-in-human outcomes of modakafusp alfa, focusing on outcomes from an expansion cohort with dosing every 4 weeks (Q4W) in patients with RRMM.2 The key findings are summarized below.
Overall, 29 patients were treated with 1.5 mg/kg Q4W modakafusp alfa: five in the dose-escalation part and 24 in the ongoing dose-expansion part. The analysis includes data from all 29 patients.
Figure 2. ORR in patients who received 1.5 mg/kg Q4W modakafusp alfa*
BCMA, B-cell maturation antigen; CR, complete response; ORR, overall response rate; PR, partial response; Q4W, every 4 weeks; VGPR, very good partial response.
*Adapted from Vogel.2
Modakafusp alfa represents a promising candidate for the treatment of patients with RRMM. The investigators considered that modakafusp alfa had a manageable safety profile, with anti-myeloma activity in heavily pre-treated patients.2 The dose optimization and potential combinations are currently being explored in the dose-escalation part of the study.3
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