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Review
. 2023 Oct;319(1):128-141.
doi: 10.1111/imr.13265. Epub 2023 Aug 21.

Antibody-mediated phagocytosis in cancer immunotherapy

Carly M Van Wagoner  1   2 , Fátima Rivera-Escalera  1   2 , Nydia C Jaimes-Delgadillo  3 , Charles C Chu  3   4 , Clive S Zent  3   4 , Michael R Elliott  1   2
Affiliations
Review

Antibody-mediated phagocytosis in cancer immunotherapy

Carly M Van Wagoner et al. Immunol Rev. 2023 Oct.

Abstract
in English, German

Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via direct cytotoxic effects. More recently, antibody-dependent cellular phagocytosis (ADCP) has been appreciated as a major mechanism of action for a number of widely-used mAbs, including anti-CD20 (rituximab, obinutuzumab), anti-HER2 (trazituzumab), and anti-CD38 (daratumumab). However, as a monotherapy these ADCP-inducing mAbs produce insufficient levels of cytotoxicity in vivo and are not curative. As a result, these mAbs are most effectively used in combination therapies. The efficacy of these mAbs is further hampered by the apparent development of drug resistance by many patients. Here we will explore the role of ADCP in cancer immunotherapy and discuss the key factors that could limit the efficacy of ADCP-inducing mAbs in vivo. Finally, we will discuss current insights and approaches being applied to overcome these limitations.

Unconjugated monoclonal antibodies (mAbs) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via direct cytotoxic effects. More recently, antibody-dependent cellular phagocytosis (ADCP) has been appreciated as a major mechanism of action for a number of widely used mAbs, including anti-CD20 (rituximab, obinutuzumab), anti-HER2 (trastuzumab), and anti-CD38 (daratumumab). However, as a monotherapy, these ADCP-inducing mAbs produce insufficient levels of cytotoxicity in vivo and are not curative. As a result, these mAbs are most effectively used in combination therapies. The efficacy of these mAbs is further hampered by the apparent development of drug resistance by many patients. Here we will explore the role of ADCP in cancer immunotherapy and discuss the key factors that could limit the efficacy of ADCP-inducing mAbs in vivo. Finally, we will discuss current insights and approaches being applied to overcome these limitations.

Keywords: cancer; immunotherapy; macrophages; monoclonal antibodies; phagocytosis.

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Conflict of interest statement

CONFLICT OF INTEREST

No conflicts to declare

Figures

Figure 1.
Figure 1.
ADCP-limiting mechanisms. Shown are three established mechanisms that serve to limit mAb-induced ADCP by phagocytes. Top: Expression of inhibitory receptors on phagocytes can be engaged and activated by interaction with ligands on target cell surface, resulting in reduced ADCP. Middle: High levels of ADCP can result in the depletion of activating FcyRs on the phagocyte surface, which reduces FcyR-dependent ADCP. Bottom, The phagocytic removal of antibody:antigen complexes (Ab:Ag) without engulfment of target cell results in the depletion of surface antigen for the antibody to bind. Created with BioRender.com
See this image and copyright information in PMC

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