Translational Study of Cell Surface Proteins in Non-Hodgkin Lymphoma Patients Treated with the First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Rituximab

Introduction

Magrolimab (Hu5F9-G4, 5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and "don't eat me" signal expressed on cancer cells. Blockade of CD47 leads to phagocytosis of tumor cells. Magrolimab synergizes with rituximab to eliminate CD20-positive lymphoma by enhancing antibody-dependent cellular phagocytosis. Magrolimab +rituximab demonstrated encouraging safety and efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab-refractory (Advani et al., NEJM 2018). CD24 is an additional "don't eat me" signal, and has been proposed as a potential target for immunotherapy (Barkal et al. Nature 2019). Here we describe immunohistochemical analysis of CD47 and CD24 in primary patient biopsies from an ongoing follow-up Phase 2 trial of Non-Hodgkin's lymphoma (including DLBCL and indolent lymphoma) patients treated with magrolimab+rituximab.

Results

By immunohistochemistry, 54 out of 54 patients assessed were positive for expression of CD47 at screening. High levels of CD47 expression were maintained during treatment with clinically-efficacious doses of magrolimab. Therapeutic response did not correlate with CD47 H-score expression levels. At screening, patients presented with highly variable levels of CD24 expression, with 40 of 54 samples showing positive staining in >30% of cells. We observed no significant correlation between CD24 expression by H-score and response to therapy (complete response + partial response) in either DLBCL or indolent lymphoma.

Conclusions

CD47 shows consistently high expression in primary biopsies from Non-Hodgkin's lymphoma patients and remains persistently high during treatment. In our Phase 2 trial, therapeutic response did not correlate with CD47 expression levels, suggesting that the degree of target expression is not a primary driver of magrolimab efficacy in Non-Hodgkin's lymphoma. Although we observe wide variation in CD24 expression within this cohort, its levels are not predictive of outcome for this disease indication. We are evaluating the expression of additional biomarkers to identify those Non-Hodgkin's lymphoma patients most likely to benefit from magrolimab+rituximab combination therapy.