Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives

Jiang, Chenyang; Sun, Hao; Jiang, Zhongxing; Tian, Wenzhi; Cang, Shundong; Yu, Jifeng

doi:10.3389/fonc.2024.1378647

Front. Oncol.

2024

DOI: 10.3389/fonc.2024.1378647

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Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives

Chenyang Jiang,

Hao Sun,

Zhongxing Jiang

et al.

Abstract: Since its initial report in 2015, CD47 has garnered significant attention as an innate immune checkpoint, raising expectations to become the next “PD-1.” The optimistic early stages of clinical development spurred a flurry of licensing deals for CD47-targeted molecules and company mergers or acquisitions for related assets. However, a series of setbacks unfolded recently, starting with the July 2023 announcement of discontinuing the phase 3 ENHANCE study on Magrolimab plus Azacitidine for higher-risk myelodysp… Show more

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The hallmarks of cancer immune evasion

Galassi,

Chan,

Vitale

et al. 2024

Cancer Cell

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The hallmarks of cancer immune evasion

Galassi,

Chan,

Vitale

et al. 2024

Cancer Cell

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Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology

Martineau,

Susini,

Marabelle

2024

Immunological Reviews

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Antagonistic monoclonal antibodies (mAbs) targeting inhibitory immune checkpoints have revolutionized the field of oncology. CTLA‐4, PD‐1, and LAG3 are three co‐inhibitory receptors, which can be expressed by subsets of T cells and which play a role in the regulation of adaptive immune responses. Blocking these immune checkpoints receptors (or their ligands) with antagonistic antibodies can lead to tumor regressions and lasting remissions in some patients with cancer. Two anti‐CTLA4, six anti‐PD1, three anti‐PD‐L1, and one anti‐LAG3 antibodies are currently approved by the FDA and EMA. Their mechanism of action, safety, and efficacy are linked to their affinity with Fc gamma receptors (FcγR) (so called “effector functions”). The anti‐CTLA‐4 antibodies ipilimumab (IgG1) and tremilimumab (IgG2a), and the anti‐PD‐L1 avelumab (IgG1) have isotypes with high affinity for activating FcγR and thereby can induce ADCC/ADCP. The effector function is required for the in vivo efficacy of anti‐CTLA4 antibodies. For anti‐PD(L)1 antibodies, where a pure antagonistic function (“checkpoint blockade”) is sufficient, some mAbs are IgG1 but have been mutated in their Fc sequence (e.g., durvalumab and atezolizumab) or are IgG4 (e.g., nivolumab and pembrolizumab) to have low affinity for FcγR. Here, we review the impact of FcγR effector function on immune checkpoint blockers safety and efficacy in oncology.

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Targeted hematopoietic stem cell depletion through SCF-blockade

Chan,

Ho,

Dib

et al. 2024

Stem Cell Res Ther

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Background Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown. Methods To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored. Results We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice. Conclusion These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide.

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Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives

Cited by 3 publications

References 100 publications

The hallmarks of cancer immune evasion

The hallmarks of cancer immune evasion

Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology

Targeted hematopoietic stem cell depletion through SCF-blockade

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