TY - JOUR
T1 - Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology
AU - Martineau, Romane
AU - Susini, Sandrine
AU - Marabelle, Aurelien
N1 - Publisher Copyright:
© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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.
AB - 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.
KW - FcγR
KW - immune checkpoint
KW - monoclonal antibody
UR - http://www.scopus.com/inward/record.url?scp=85211432072&partnerID=8YFLogxK
U2 - 10.1111/imr.13427
DO - 10.1111/imr.13427
M3 - Review article
AN - SCOPUS:85211432072
SN - 0105-2896
VL - 328
SP - 334
EP - 349
JO - Immunological Reviews
JF - Immunological Reviews
IS - 1
ER -