magrolimab (ONO-7913)

CD47-targeted combinations demonstrate encouraging early phase efficacy and manageable safety in hematologic malignancies, with signals of benefit in higher-risk MDS, TP53-mutant AML, relapsed/refractory DLBCL, and rituximab-refractory iNHL. However, recent Phase III trials in newly diagnosed AML Daver et al. [27], and Zeidner et al. [26] did not confirm this benefit, underscoring that CD47 blockade remains investigational and requires validation in rigorously designed randomized studies.

Hu5F9-G4 demonstrates potential as a therapeutic agent in CRC by promoting M2d-to-M1 macrophage polarization, suppressing tumor progression, and influencing the autophagy pathway. These findings highlight CDKN1A and MAP1LC3B as promising targets for CRC therapy.

Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

HCB101 demonstrates high-affinity binding to CD47, robustly promotes macrophage-mediated phagocytosis of tumor cells without affecting red blood cells and exhibits unique advantages over current CD47-targeting agents, including Hu5F9-G4, TTI-622, and ALX148. Additionally, HCB101 treatment increased the M1/M2 macrophage ratio in the tumor microenvironment, suggesting repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype. No dose-limiting toxicities or hematologic adverse effects were observed in murine or non-human primate studies.

These findings emphasize the need for awareness and adaptation in immunohematology practices as anti-CD47 drugs continue to advance in clinical development, and highlight the utility of antigen masking strategies to enhance the safe administration of blood products to treated patients.

Immune checkpoint inhibitors (ICIs), such as anti-PD-1 nivolumab and anti-CD47 magrolimab, combined with hypomethylating agents (HMAs), enhance T-cell activity and phagocytosis, especially in TP53-mutated AML. Integrating these innovations may transform AML into a chronic condition, bridging preclinical potential to clinical impact. In this review, we aim to evaluate mechanisms, challenges, and future directions of immunotherapies in AML with highlighting ICIs and vaccination to improve therapeutic outcomes.

P1/2, N=272, Active, not recruiting, Hoffmann-La Roche | Trial completion date: May 2026 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

When combined with a prophagocytic signal from an anti-CD20 antibody rituximab, it has shown activity in relapsed or refractory FL and MZL. In this phase 1 study, adding the BCL2-inhibitor venetoclax to magrolimab and the anti-CD20 antibody obinutuzumab resulted in complete responses in 6 of 10 (60%) evaluable patients with FL, MZL or CLL. Notably, we did not observe increased risk of infections previously reported from studies of magrolimab in acute myeloid leukaemia and higher risk myelodysplastic syndromes.

To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models-AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). Interestingly, the two models that demonstrated improvement in survival with Magro harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is being evaluated for use in other malignancies, future studies may focus on investigating the importance of biomarker-based patient selection.

Clinical trials involving PD-1 inhibition with nivolumab combined with SOC failed to increase survival...By studying time-varying efficacy with the same half-life as the anti-CD47 antibody Hu5F9-G4, our model predicts that repeated dosing of anti-CD47 provides sustained control of tumor growth. We propose that targeting TAMs by enhancing their antitumoral properties is a highly promising avenue to treat glioblastoma and warrants future clinical development. Together, our results provide proof-of-concept that mechanistic mathematical modeling can uncover the mechanisms driving treatment outcomes and explore the potential of novel treatment strategies for hard-to-treat tumors like glioblastoma.

P2, N=36, Terminated, Gilead Sciences | Completed --> Terminated; This study was terminated early due to the Sponsor's decision to discontinue development of the investigational drug and close the program.

The triplet regimen was safe but did not lead to promising survival outcomes.