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Published on: November 12, 2019
Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies
E C Pietsch1, J Dong2, R Cardoso3
1Oncology Discovery, Janssen Research and Development, Spring House, PA, USA.
Abstract:
CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices.
Insights
Targeting CD47, a protein on cancer cells, shows therapeutic potential. Blocking CD47 with antibodies requires Fc effector function for anti-cancer activity and causes side effects like reduced red blood cells.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- CD47 is a cell surface protein that prevents phagocytosis by interacting with SIRPα on phagocytes.
- Elevated CD47 expression in hematological malignancies suggests its role in immune evasion.
- Targeting CD47 presents a potential strategy for cancer immunotherapy.
Purpose of the Study:
- To develop and characterize novel anti-CD47 monoclonal antibodies (mAbs) that block the CD47-SIRPα interaction.
- To evaluate the anti-cancer activity of these mAbs in vitro and in vivo.
- To determine the role of Fc effector function in the therapeutic efficacy and potential side effects of anti-CD47 therapy.
Main Methods:
- Discovery of three unique anti-CD47 mAbs with high affinity and no hemagglutination or platelet aggregation.
- Cloning of mAbs into effector-silent and effector-competent Fc backbones.
- In vitro and in vivo efficacy studies, including a non-human primate study to assess red blood cell effects.
Main Results:
- Effector function-competent anti-CD47 mAbs showed potent in vitro and in vivo anti-cancer activity.
- Effector function-silent mAbs exhibited minimal therapeutic activity.
- A non-human primate study demonstrated significant red blood cell reduction with effector-competent mAbs, but not with effector-silent mAbs.
Conclusions:
- Blocking CD47 is a promising anti-cancer strategy.
- The therapeutic anti-cancer activity of anti-CD47 mAbs is dependent on Fc effector function.
- Fc effector function also mediates the observed side effects on red blood cells.
