Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy

Sabatos-Peyton, Catherine; Nevin, James; Brock, Ansgar; Venable, John D.; Tan, Dewar J.; Kassam, Nasim; Xu, Fangmin; Taraszka, John A.; Wesemann, Luke; Pertel, Thomas; Acharya, Nandini; Klapholz, Max; Etminan, Yassaman; Jiang, Xiaomo; Huang, Yu‐Hwa; Blumberg, Richard S.; Kuchroo, Vijay K.; Anderson, Ana C.

doi:10.1080/2162402x.2017.1385690

Cited by 90 publications

(84 citation statements)

References 24 publications

(44 reference statements)

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“…CEACAM1-TIM-3 interactions have been biochemically mapped to the GFCC'C" interface of both molecules that overlaps with those involved in homophilic binding of CEACAM1 and the phosphatidylserine binding sites on TIM-3 [15,24,142]. Interestingly, the binding epitope of anti-TIM-3 antibodies that function as effective anti-cancer agents map to the CEACAM1 binding site on TIM-3 suggesting that targeting TIM-3 requires disabling TIM-3 interactions with CEACAM1 and/or phosphatidylserine [143]. Notably, a single nucleotide polymorphism in TIM-3 that causes a substitution at residue 101 (T101I) maps outside the CEACAM1-TIM-3 binding interface but is associated with an increased risk of inflammatory bowel disease [15].…”

Section: Ceacam1 Regulates T Cell Activation and Mediates Tolerance-mentioning

confidence: 99%

CEACAM1 structure and function in immunity and its therapeutic implications

Kim

Huang

Gandhi

et al. 2019

Seminars in Immunology

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The type I membrane protein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) distinctively exhibits significant alternative splicing that allows for tunable functions upon homophilic binding. CEACAM1 is highly expressed in the tumor environment and is strictly regulated on lymphocytes such that its expression is restricted to activated cells where it is now recognized to function in tolerance pathways. CEACAM1 is also an important target for microbes which have co-opted these attributes of CEACAM1 for the purposes of invading the host and evading the immune system. These properties, among others, have focused attention on CEACAM1 as a unique target for immunotherapy in autoimmunity and cancer. This review examines recent structural information derived from the characterization of CEACAM1:CEACAM1 interactions and heterophilic modes of binding especially to microbes and how this relates to CEACAM1 function. Through this, we aim to provide insights into targeting CEACAM1 for therapeutic intervention.

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Section: Ceacam1 Regulates T Cell Activation and Mediates Tolerance-mentioning

confidence: 99%

CEACAM1 structure and function in immunity and its therapeutic implications

Kim

Huang

Gandhi

et al. 2019

Seminars in Immunology

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“…It has been shown that functionally efficacious anti-murine and anti-human TIM-3 antibodies interfere with binding to both PtdSer and CEACAM1, 12 although none of the anti-TIM -3 antibodies tested by Sabatos-Peyton et al (2017) interfered with the binding of TIM-3 and Gal-9. However, Gal-9 has been hypothesized to be trafficked by TIM-3 and play an important role in TIM-3 signaling.…”

Section: Introductionmentioning

confidence: 98%

“…However, Gal-9 has been hypothesized to be trafficked by TIM-3 and play an important role in TIM-3 signaling. 12,13 Gal-9 also has a role in the inhibition of T cell responses 4 and may increase tumorgenicity via T cell dysfunction. 9,14 Therefore, anti-tumor efficacy could potentially be improved if the interaction of TIM-3 with Gal-9 were blocked in addition to the interaction of TIM-3 with PtdSer and CEACAM1.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of M6903, an antagonistic anti–TIM-3 monoclonal antibody

et al. 2020

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T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional and exhausted T cells, and engagement of TIM-3 with its ligands promotes TIM-3-mediated T cell inhibition. Antagonistic ligand-blocking anti-TIM-3 antibodies have the potential to abrogate T cell inhibition, activate antigen-specific T cells, and enhance anti-tumor immunity. Here we describe M6903, a fully human anti-TIM-3 antibody without effector function and with high affinity and selectivity to TIM-3. We demonstrate that M6903 blocks the binding of TIM-3 to three of its ligands, phosphatidylserine (PtdSer), carcinoembryonic antigen cell adhesionrelated molecule 1 (CEACAM1), and galectin 9 (Gal-9). These results are supported by an atomic resolution crystal structure and functional assays, which demonstrate that M6903 monotherapy enhanced T cell activation. This activation was further enhanced by the combination of M6903 with bintrafusp alfa, a bifunctional fusion protein that simultaneously blocks the transforming growth factorβ (TGF-β) and programmed death ligand 1 (PD-L1) pathways. M6903 and bintrafusp alfa combination therapy also enhanced anti-tumor efficacy in huTIM-3 knock-in mice, relative to either monotherapy. These in vitro and in vivo data, along with favorable pharmacokinetics in marmoset monkeys, suggest that M6903 as a monotherapy warrants further pre-clinical assessment and that M6903 and bintrafusp alfa may be a promising combination therapy in the clinic. ARTICLE HISTORY

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“…TIM-3 mediates its suppressive activity on immune cells via its ligands that include phosphatidylserine, CEACAM-1 and the widely expressed ligand galectin-9 23,24 . TIM-3 is expressed on activated T cells and its signaling on cytotoxic T cells leads to an exhausted phenotype, characterized by a reduction in proliferation, decreased production of effector cytokines and apoptosis of effector T cells 25 .…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy

Cited by 90 publications

References 24 publications

CEACAM1 structure and function in immunity and its therapeutic implications

CEACAM1 structure and function in immunity and its therapeutic implications

Identification and characterization of M6903, an antagonistic anti–TIM-3 monoclonal antibody

TIM-3 expression in breast cancer

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