The effects of monoclonal anti‐CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia

Brierley, Charlotte; Staves, Julie; Roberts, Corran; Johnson, Helen; Vyas, Paresh; Goodnough, Lawrence T.; Murphy, M. F.

doi:10.1111/trf.15397

Cited by 87 publications

(83 citation statements)

References 19 publications

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“…As seen with CD38 blocking agents, including daratumumab, [7][8][9] CD47 blocking agents generate panreactivity in IAT, interfering with pretransfusion compatibility testing. 10,11,16,17 While plasma from patients treated with daratumumab typically shows weak reactivity in IAT, 18 plasma from patients treated with Hu5F9-G4 or ALX148 exhibits strong reactivity in IAT. 10,16,17 Similarly, in our study, strong reactivity (3+) in gel IAT was observed in the plasma from all four patients treated with ALX148.…”

Section: Discussionmentioning

confidence: 99%

“…Phenotyping of patient RBCs for extended antigen-matched blood transfusion can be accomplished using antigen typing reagents at the IS or RT phases, even after ALX148 administration. The increasingly widespread T A B L E 3 Comparison of interference in pretransfusion compatibility testing and mitigation strategies between Hu5F9-G4 10,11 and ALX148 (our study) [15][16][17] Hu5F9-G4 ALX148 use of MoAbs and fusion proteins with unintended binding to RBCs poses a growing challenge to blood banks. International efforts should be undertaken to investigate the potential of each drug to interfere with pretransfusion compatibility testing and establish a guideline to solve the problem.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] Recently, the interference of a humanized anti-CD47 MoAb of the IgG4 isotype (Hu5F9-G4) in pretransfusion compatibility testing has been described. 10,11 Multiple rounds of adsorption with papain-treated allogeneic RBCs and/or indirect antiglobulin testing (IAT) using Gamma-clone anti-IgG (Immucor, Norcross, GA) without IgG4 reactivity resolved the Hu5F9-G4 interference. 10 The interference of SIRPα-Fc fusion proteins in pretransfusion compatibility testing also needs to be characterized, because their RBC-binding profiles could differ from those of anti-CD47 MoAbs.…”

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Assessing and mitigating the interference of ALX148, a novel CD47 blocking agent, in pretransfusion compatibility testing

et al. 2020

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Funding information ALX148, soluble CD47, and high-affinity SIRP monomers were provided by ALX Oncology Background ALX148, a novel CD47 blocking agent, is in clinical development for the treatment of advanced solid tumors and lymphoma. Because CD47 is highly expressed on red blood cells (RBCs), its therapeutic blockade can potentially interfere with pretransfusion compatibility testing. This study describes the interference of ALX148 in pretransfusion compatibility testing and evaluates the methods used for mitigating such interference. Study Design and Methods: Routine serologic tests were performed on six samples from four patients treated with ALX148. Antibody screening tests were performed on ALX148-spiked plasma, and RBC testing including antigen typing was performed on ALX148-coated RBCs. Soluble CD47 or high-affinity signal regulatory protein α (SIRPα) monomers were used to remove the falsepositive reactivity of ALX148-spiked plasma with or without anti-E. Results: ALX148 caused false-positive reactivity in antibody screening using indirect antiglobulin testing (IAT) and two-stage papain testing. However, falsepositive reactivity was not observed at the immediate spin (IS), room temperature (RT), and 37°C phases. Direct antiglobulin testing, autologous controls, and eluates showed positive results. ALX148 did not affect blood group antigen typing performed at the IS or RT phases. The use of 50-to 100-fold molar excess of soluble CD47 or 300-fold molar excess of high-affinity SIRPα monomers removed false-positive reactivity in IAT without affecting anti-E detection. Conclusion: ALX148 generates false-positive reactivity in IAT, interfering with pretransfusion compatibility testing. The use of soluble CD47 or highaffinity SIRPα monomers can resolve the interference without possibly missing clinically significant alloantibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Assessing and mitigating the interference of ALX148, a novel CD47 blocking agent, in pretransfusion compatibility testing

et al. 2020

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“…Enthusiasm surrounding the clinical utility of SIRPa/CD47 inhibition is somewhat tempered by expression of CD47 on erythrocytes and platelets, and the associated risk of hemolysis and thrombocytopenia (21,42,45). The Fc domain of hSIRPa-Fc-CD40L does not bind effector Fc receptors ( Supplementary Table S2), and in vitro studies did not reveal evidence of hemolysis in human or cynomolgus macaque erythrocytes ( Supplementary Fig.…”

Section: Safety and Activity Of Sirpa-fc-cd40l In Nonhuman Primatesmentioning

confidence: 99%

CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity

Silva

Fromm

Shuptrine

et al. 2020

Cancer Immunology Research

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Disrupting the binding of CD47 to SIRPa has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPa blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8 þ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPa and CD40L, adjoined by a central Fc domain, termed SIRPa-Fc-CD40L. SIRPa-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPa-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPa-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo. These data illustrated that whereas CD47/SIRPa inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage-and T-cell-mediated immunity that significantly enhanced durable tumor control and rejection.

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“…Hu5F9-G4 is a novel anti-CD47 monoclonal IgG4 antibody under evaluation in six studies in the United States and United Kingdom. 3,4 In the UK, the CAMELLIA study is a Phase 1 dose escalation trial of Hu5F9-G4 in haematologic malignancies including relapsed/refractory acute myeloid leukaemia/highrisk myelodysplasia (NCT02678338).…”

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confidence: 99%

Two case reports involving therapeutic monoclonal anti‐CD47 (Hu5F9‐G4), it's effect on compatibility testing and subsequent selection of components for transfusion

Reyland

Dwight

Bullock

et al. 2020

Transfusion Medicine

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The effects of monoclonal anti‐CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia

Abstract: BACKGROUND: CD47 is a novel therapeutic target in Abbreviations: AML = acute myeloid leukemia; B-NHL = B-cell non-Hodgkin lymphoma; DAT = direct antiglobulin test; DTT = dithiothreitol; Hb = hemoglobin; IAT = indirect antiglobulin test. From the

Cited by 87 publications

References 19 publications

Assessing and mitigating the interference of ALX148, a novel CD47 blocking agent, in pretransfusion compatibility testing

Assessing and mitigating the interference of ALX148, a novel CD47 blocking agent, in pretransfusion compatibility testing

CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity

Two case reports involving therapeutic monoclonal anti‐CD47 (Hu5F9‐G4), it's effect on compatibility testing and subsequent selection of components for transfusion

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