Abstract 3825: INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3

Waight, Jeremy D.; Iyer, Priyadarshini; Breous-Nystrom, Ekaterina; Riordan, Christina; Findeis, Mark A.; Underwood, Dennis; Connolly, Joseph D.; Sanicola-Nadel, Michele; Nastri, Horacio; Scherle, Peggy; Hollis, Gregory; Huber, Reid; Stein, Robert B.; Dijk, Mark van; Wilson, Nicholas S.

doi:10.1158/1538-7445.am2018-3825

Cited by 14 publications

(9 citation statements)

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“…Several groups are currently pursuing the development of therapeutic TIM-3 antibodies to promote anti-tumor immune responses, mostly in combination with PD-1 or PD-L1 antibodies — with the assumption that they will reverse a co-inhibitory signaling effect of TIM-3 [ 3 , 8 , 11 ]. Most TIM-3 antibodies under investigation have been shown to recognize the PS-binding site of TIM-3 [ 37 , 82 ], including Sym023 [ 83 ], BGB-A425 [ 84 ], ICAGN02390 [ 85 ], IBI104 [ 86 ], and LY3321367 [ 87 ]. Counterintuitively, our results suggest that these antibodies might actually impair T cell responses by blocking PS-induced co-stimulatory TIM-3 signaling — as indeed we observed for F38.2E2 in Figure 6 .…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylserine binding directly regulates TIM-3 function

Smith

Krishnamurthy

et al. 2021

Biochemical Journal

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Co-signaling receptors for the T cell receptor (TCR) are important therapeutic targets, with blockade of co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood potential therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which of TIM-3's several proposed regulatory ligands is/are relevant for signaling is unclear, and different studies have reported TIM-3 as a co-inhibitory or co-stimulatory receptor in T cells. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following TCR stimulation in Jurkat cells, and that this activity is regulated by binding to phosphatidylserine (PS). TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings clarify the importance of PS as a functional TIM-3 ligand, and may inform the future exploitation of TIM-3 as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Phosphatidylserine binding directly regulates TIM-3 function

Smith

Krishnamurthy

et al. 2021

Biochemical Journal

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“…In pre-clinical mouse models of colorectal cancer (MC38 and CT26), the effects of “silent” Fc vs. “competent” Fc on TIM-3 antibody-mediated anti-tumor activity with or without anti-PD-1 antibody treatment were evaluated by several groups (106, 107). The results showed that the combination of “Fc-silent” TIM-3 Ab with PD-1 Ab led to significantly more synergistic tumor-inhibitory effects than the one with “competent” Fc, while TIM-3 blocking Ab monotherapy demonstrated marginal anti-tumor efficacy.…”

Section: Immune Checkpoint Molecules and Their Therapeutic Antibodiesmentioning

confidence: 99%

FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

et al. 2019

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T cells play critical roles in anti-tumor immunity. Up-regulation of immune checkpoint molecules (PD-1, PD-L1, CTLA-4, TIM-3, Lag-3, TIGIT, CD73, VISTA, B7-H3) in the tumor microenvironment is an important mechanism that restrains effector T cells from the anti-tumor activity. To date, immune checkpoint antibodies have demonstrated significant clinical benefits for cancer patients treated with mono- or combination immunotherapies. However, many tumors do not respond to the treatment well, and merely blocking the immune suppression pathways by checkpoint-regulatory antibodies may not render optimal tumor growth inhibition. Binding of the antibody Fc-hinge region to Fc gamma receptors (FcγRs) has been shown to exert a profound impact on antibody function and in vivo efficacy. Investigation of immune checkpoint antibodies regarding their effector functions and impact on therapeutic efficacy has gained more attention in recent years. In this review, we discuss Fc variants of antibodies against immune checkpoint targets and the potential mechanisms of how FcγR-binding could influence the anti-tumor activity of these antibodies.

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“…Crucially, the epitopes of most functional TIM-3 antibodies have been shown to map to the PS binding site [34,80] but do not affect galectin-9 binding, arguing that blocking PS binding is key to conferring functional efficacy of the antibodies in promoting immune responses. Most TIM-3 antibodies currently in the clinic block PS binding to the receptor [3], including Sym023 [81], BGB-A425 [82], ICAGN02390 [83], and LY3321367 [84]. Our findings argue that these antibodies most likely block a signaling response to PS binding.…”

Section: Discussionmentioning

confidence: 66%

Phosphatidylserine binding regulates TIM-3 effects on T cell receptor signaling

Smith

Krishnamurthy

et al. 2021

Preprint

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Co-signaling receptors for the T cell receptor are important therapeutic targets, with blocking co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which ligands are relevant for TIM-3 signaling is unclear, and different studies have reported it as co-inhibitory or co-stimulatory. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following T cell receptor stimulation in Jurkat cells, and is regulated by phosphatidylserine (PS) binding. TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings help clarify conflicting literature results with TIM-3, and inform its exploitation as a therapeutic target.

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Abstract 3825: INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3

Cited by 14 publications

References 0 publications

Phosphatidylserine binding directly regulates TIM-3 function

Phosphatidylserine binding directly regulates TIM-3 function

FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

Phosphatidylserine binding regulates TIM-3 effects on T cell receptor signaling

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