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Background <p>Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies.</p> Methods <p>Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors.</p> Results <p>We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8<sup>+</sup> T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8<sup>+</sup> T cells by decreasing activating and inhibitory FcγRs.</p> Conclusions <p>Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing.</p> Graphical Abstract <p></p> <p><UnorderedList Mark="Bullet"> <ItemContent> <p>FcγRIIB-selective blockade enhances&#xa0;αCTLA-4-mediated Treg depletion, myeloid reprogramming, and effector CD8<sup>+</sup>&#xa0;T cell activation by increasing the activating-to-inhibitory (A:I)&#xa0;FcγR&#xa0;engagement&#xa0;ratio.</p> </ItemContent> <ItemContent> <p>Conversely, pan-FcγR&#xa0;blockade&#xa0;protects&#xa0;αPD-1-coated T cells from macrophage phagocytosis and&#xa0;from&#xa0;αPD-1 removal via&#xa0;trogocytosis,&#xa0;thereby&#xa0;increasing intratumoral activated CD8<sup>+</sup>&#xa0;T cells&#xa0;by&#xa0;decreasing activating and inhibitory&#xa0;FcγRs.</p> </ItemContent> </UnorderedList></p>

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Tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月25日

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  • Robert J. Oldham,
  • Linda Mårtensson,
  • Monika Semmrich,
  • Niyaz Yoosuf,
  • Petra Holmkvist,
  • Lara V. Graham,
  • Martin C. Taylor,
  • Kirstie L. S. Cleary,
  • Mona Yazdani,
  • Josephine F. Buckingham,
  • Ali Roghanian,
  • Ingrid Karlsson,
  • Stephen A. Beers,
  • Ingrid Teige,
  • Mark S. Cragg,
  • Björn Frendéus

摘要

Background

Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies.

Methods

Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors.

Results

We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8+ T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs.

Conclusions

Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing.

Graphical Abstract

FcγRIIB-selective blockade enhances αCTLA-4-mediated Treg depletion, myeloid reprogramming, and effector CD8+ T cell activation by increasing the activating-to-inhibitory (A:I) FcγR engagement ratio.

Conversely, pan-FcγR blockade protects αPD-1-coated T cells from macrophage phagocytosis and from αPD-1 removal via trogocytosis, thereby increasing intratumoral activated CD8+ T cells by decreasing activating and inhibitory FcγRs.