Tumor suppression of novel anti–PD-1 antibodies mediated through CD28 costimulatory pathway

Fenwick, Craig; Loredo-Varela, Juan-Luis; Joo, Victor; Pellaton, Céline; Farina, A.; Rajah, Navina; Esteves-Leuenberger, Line; Decaillon, Thibaut; Suffiotti, Madeleine; Noto, Alessandra; Ohmiti, Khalid; Gottardo, Raphaël; Weissenhorn, Winfríed; Pantaleo, Giuseppe

doi:10.1084/jem.20182359

Cited by 25 publications

(22 citation statements)

References 56 publications

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“…In vitro studies using the cells of HIV‐infected patients have established a clear proof of principle benefit in using anti‐PD‐1 or PDL‐1 antibodies to relieve exhaustion and enhance HIV‐antigen‐specific functionality and proliferation. Our own in vitro studies show that the combination of classical blocking anti‐PD‐1 antibodies with novel antagonistic anti‐PD‐1 antibodies that are non‐blocking of the PD‐1/PDL‐1 interaction synergize to relieve functional exhaustion of HIV‐specific CD8 T cells and represent an exciting option for HIV immunotherapy . In vivo PD‐1 blockade studies with SIV‐infected macaques demonstrated a rapid expansion and functional quality of virus‐specific CD8 T cells in both the blood and gut tissue.…”

Section: Exploiting Pd‐1 Targeting To Purge the Hiv Reservoirmentioning

confidence: 94%

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T‐cell exhaustion in HIV infection

Fenwick

Joo

Jacquier

et al. 2019

Immunological Reviews

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274

219

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The T-cell response is central in the adaptive immune-mediated elimination of pathogen-infected and/or cancer cells. This activated T-cell response can inflict an overwhelming degree of damage to the targeted cells, which in most instances leads to the control and elimination of foreign invaders. However, in conditions of chronic infection, persistent exposure of T cells to high levels of antigen results in a severe T-cell dysfunctional state called exhaustion. T-cell exhaustion leads to a suboptimal immunemediated control of multiple viral infections including the human immunodeficiency virus (HIV). In this review, we will discuss the role of T-cell exhaustion in HIV disease progression, the long-term defect of T-cell function even in aviremic patients on antiretroviral therapy (ART), the role of exhaustion-specific markers in maintaining a reservoir of latently infected cells, and exploiting these markers in HIV cure strategies. K E Y W O R D S chronic viral infection, HIV, immune checkpoint inhibitors, PD-1, T-cell exhaustionThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Exploiting Pd‐1 Targeting To Purge the Hiv Reservoirmentioning

confidence: 94%

“…Our own laboratory recently reported a direct evaluation of signaling in truly exhausted T cells with elevated levels of PD‐1 from a chronically infected HIV donor . T‐cell activation in concert with PD‐1 ligation by PDL‐1 suppressed signaling event in both the TCR and CD28 pathways.…”

Section: Major Signaling Pathways Involved In T‐cell Exhaustionmentioning

confidence: 99%

T‐cell exhaustion in HIV infection

Fenwick

Joo

Jacquier

et al. 2019

Immunological Reviews

Self Cite

274

219

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“…In fact, a recent paper reported a novel mechanism by which PD-L1 non-blocking anti-PD-1 mAbs can show favorable anti-tumor activity. [24] In another recent publication, researchers describe a set of potent macrocyclic peptide and small-molecule PD-1/PD-L1 inhibitors, one of which induced cytokine production (IL-2 and IFN-γ) and T cell proliferation at levels comparable to pembrolizumab. [25] We suspect the unique binding properties observed for many of the antibodies studied here will translate to similarly unique biological activity at the cellular and potential therapeutic level.…”

Section: Plos Onementioning

confidence: 99%

Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors

et al. 2020

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Here we describe an industry-wide collaboration aimed at assessing the binding properties of a comprehensive panel of monoclonal antibodies (mAbs) against programmed cell death protein 1 (PD-1), an important checkpoint protein in cancer immunotherapy and validated therapeutic target, with well over thirty unique mAbs either in clinical development or market-approved in the United States, the European Union or China. The binding kinetics of the PD-1/mAb interactions were measured by surface plasmon resonance (SPR) using a Carterra LSA instrument and the results were compared to data collected on a Biacore 8K. The effect of chip type on the SPR-derived binding rate constants and affinities were explored and the results compared with solution affinities from Meso Scale Discovery (MSD) and Kinetic Exclusion Assay (KinExA) experiments. When using flat chip types, the LSA and 8K platforms yielded near-identical kinetic rate and affinity constants that matched solution phase values more closely than those produced on 3D-hydrogels. Of the anti-PD-1 mAbs tested, which included a portion of those known to be in clinical development or approved, the affinities spanned from single digit picomolar to nearly 425 nM, challenging the dynamic range of our methods. The LSA instrument was also used to perform epitope binning and ligand competition studies which revealed over ten unique competitive binding profiles within this group of mAbs.

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“…There are other membrane-expressed receptor-ligand pair molecules with opposing function (e.g., KIR/NKG2-HLA-I pairs) and even 2B4-CD48 pair can mediate dual function depending on their association with different adaptor molecules (e.g., presence or absence of intracytoplasmic SAP) [46,[84][85][86][87], thus revealing how the immune system has evolved to use even a single molecule in multiple ways depending not only on its integrated interaction with intracellular adaptors, but also with surface molecules. For example, PD-1 inhibitory function is mediated by its association with CD28 and it has been shown that antagonist anti-PD-1 (non-blocking the PD-1/PDL-1 interaction) mAbs are able to block CD28-PD-1-association finally unleashing NK cell activity in the presence of PD-1/PDL-1 engagement [88].…”

Section: Lfa-1 Mediated Inhibition Of Nk Cell Degranulation: Multi-fumentioning

confidence: 99%

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Zamai

Zotto

Buccella

et al. 2020

Cells

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The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.

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Tumor suppression of novel anti–PD-1 antibodies mediated through CD28 costimulatory pathway

Cited by 25 publications

References 56 publications

T‐cell exhaustion in HIV infection

T‐cell exhaustion in HIV infection

Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

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