Targeting the Antibody Checkpoints to Enhance Cancer Immunotherapy–Focus on FcγRIIB

Teige, Ingrid; Mårtensson, Linda; Frendéus, Björn

doi:10.3389/fimmu.2019.00481

Cited by 34 publications

(32 citation statements)

References 112 publications

(133 reference statements)

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“…One factor influencing these signals is the affinity of the respective IgG isotype to the distinct FcγRs present on the cell surface. This led to the development of the concept of the so called A/I ratio as a prediction of the outcome of binding of IgG molecules of a given isotype based on its affinities to the inhibitory and activating receptors, respectively (13)(14)(15). Based on the A/I ratio concept mathematical models have been developed predicting IgG activity (16).…”

Section: Introductionmentioning

confidence: 99%

There Is (Scientific) Strength in Numbers: A Comprehensive Quantitation of Fc Gamma Receptor Numbers on Human and Murine Peripheral Blood Leukocytes

2020

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Antibodies are essential mediators of immunological defense mechanisms, are clinically used as therapeutic agents, but are also functionally involved in various immune-mediated disorders. Whereas IgG antibodies accomplish some of their biological tasks autonomously, many functions depend on their binding to activating and inhibitory Fcγ receptors (FcγR). From a qualitative point of view expression patterns of FcγR on immunologically relevant cell types are well-characterized both for mice and humans. Surprisingly, however, there is only quite limited information available on actual quantities of FcγR expressed by the different leukocyte populations. In this study we provide a comprehensive data set assessing quantitatively how many individual human and mouse FcγRs are expressed on B cells, NK cells, eosinophils, neutrophils, basophils and both classical, and non-classical monocytes under steady state conditions. Moreover, among human donors we found two groups with different expression levels of the inhibitory FcγRIIb on monocytes which appears to correlate with haplotypes of the activating FcγRIIIa.

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Section: Introductionmentioning

confidence: 99%

There Is (Scientific) Strength in Numbers: A Comprehensive Quantitation of Fc Gamma Receptor Numbers on Human and Murine Peripheral Blood Leukocytes

2020

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“…2,10 However, the first co-inhibitory receptor that was discovered and characterized was FcγRIIb in B cells. [11][12][13][14] Although blocking the FcγRIIb receptor is beneficial for some anti-cancer antibody therapies, 15 it is not targeted in current checkpoint blockade approaches, as promoting B cell responses is thought to be rarely effective in cancer. Nevertheless, the concept of co-inhibitory checkpoints originated with these studies and theories about the regulation of B cell responses.…”

Section: Blocking Negative Feedback Signals (From Co-inhibitors) Fomentioning

confidence: 99%

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

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“…Physiologically, antibody multimerization is driven by FcγRIIB engagement. 40 Hence, we treated TILs with an Fc-engineered αOX40 human IgG1 antibody, termed αOX40_v12, that contains six mutations leading to increased affinity to FcγRIIB. 18 In contrast to the paratope-sharing wild-type counterpart, Fc-engineered αOX40_v12 potently stimulated TIL proliferation and activation in this study.…”

Section: Discussionmentioning

confidence: 99%

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

Carrascosa

Beek

Ruiter

et al. 2020

J Immunother Cancer

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BackgroundOX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials.MethodsUsing lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs).ResultsHere, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40_v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40_v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40_v12.ConclusionsOX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy.

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Targeting the Antibody Checkpoints to Enhance Cancer Immunotherapy–Focus on FcγRIIB

Cited by 34 publications

References 112 publications

There Is (Scientific) Strength in Numbers: A Comprehensive Quantitation of Fc Gamma Receptor Numbers on Human and Murine Peripheral Blood Leukocytes

There Is (Scientific) Strength in Numbers: A Comprehensive Quantitation of Fc Gamma Receptor Numbers on Human and Murine Peripheral Blood Leukocytes

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

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