An Inhibitor of CD28–CD80 Interactions Impairs CD28-Mediated Costimulation of Human CD4 T Cells

Fine, Jay S.; Macosko, Heather D.; Justice, Luminita; Chou, Chuan‐Chu; Jenh, Chung‐Her; Narula, Satwant K.; Zavodny, Paul J.

doi:10.1006/cimm.1998.1403

Cited by 4 publications

(2 citation statements)

References 34 publications

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“…Efforts to design small‐molecule inhibitors targeting the CD28:B7 interactions began during the late nineties . Although initial efforts resulted in either weak or nonspecific inhibitors, a major breakthrough came from Wyeth Research (part of Pfizer Inc). They reported the discovery and characterization of anti‐B7‐1 small molecules with nanomolar activity .…”

Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 99%

Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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Modulation of T‐cell immune functions by blocking key immune checkpoint protein interactions using monoclonal antibodies (mAbs) has been an innovative immunotherapeutic strategy. T‐cells are regulated by different checkpoint proteins at the immunological synapse including the B7 ligands (B7‐1 or CD80 and B7‐2 or CD86), which is discussed in this review. These ligands are typically expressed on antigen presenting cells and interact with CD28 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) receptors on T‐cells. Their interactions with CD28 trigger a costimulatory signal that potentiates T‐cell activation, function and survival in response to cognate antigen. In addition, their interactions with CTLA‐4 can also inhibit certain effector T‐cell responses, particularly in response to sustained antigen stimulation. Through these mechanisms, the balance between T‐cell activation and suppression is maintained, preventing the occurrence of immunopathology. Given their crucial roles in immune regulation, targeting B7 ligands has been an attractive strategy in cancer and autoimmunity. This review presents an overview of the essential roles of B7‐1, highlighting the therapeutic benefits of modulating this protein in immunotherapy, and reviewing earlier and state‐of‐the‐art efforts in developing anti‐B7‐1 inhibitors. Finally, we discuss the challenges facing the design of selective B7‐1 inhibitors and present our perspectives for future developments.

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Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 99%

Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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“…One of the earliest efforts to block the CD28 costimulatory PPI were done at Schering-Plough by a scintillation proximity assay (SPA) based HTS testing for the ability to inhibit the binding of CD28-Ig to CD80-Ig using a natural product library [301]. A selected microbially-sourced cyclic polypeptide, NP1835-2, was shown to concentration-dependently inhibit T cell proliferation, surface activation marker expression, and the production of several T cell cytokines [302]. Here, we will focus on nonpeptidic SMPPIIs identified afterwards.…”

Section: Small-molecule Inhibitors For Costimulatory and Coinhibitmentioning

confidence: 99%

Toward Small-Molecule Inhibition of Protein–Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions

Bojadzic

Buchwald

2018

CTMC

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Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable. Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility of such approaches have been identified through various strategies for a number of cosignaling interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s. Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models (DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of such approaches in immunomodulation. They can result in products that are easier to develop/ manufacture and are less likely to be immunogenic or encounter postmarket safety events than corresponding biologics, and, contrary to them, can even become orally bioavailable.

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High-Affinity Small Molecule Inhibitors of T Cell Costimulation: Compounds for Immunotherapy

Huxley¹,

Sutton²,

Debnam³

et al. 2004

Chemistry & Biology

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Costimulatory molecules are important regulators of T cell activation and thus favored targets for therapeutic manipulation of immune responses. One of the key costimulatory receptors is CD80, which binds the T cell ligands, CD28, and CTLA-4. We describe a set of small compounds that bind with high specificity and low nanomolar affinity to CD80. The compounds have relatively slow off-rates and block both CD28 and CTLA-4 binding, implying that they occlude the shared ligand binding site. The compounds inhibit proinflammatory cytokine release in T cell assays with submicromolar potency, and as such, they represent promising leads for the development of novel therapeutics for immune-mediated inflammatory disease. Our results also suggest that other predominantly beta proteins, such as those that dominate the cell surface, may also be accessible as potentially therapeutic targets.

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An Inhibitor of CD28–CD80 Interactions Impairs CD28-Mediated Costimulation of Human CD4 T Cells

Cited by 4 publications

References 34 publications

Targeting B7‐1 in immunotherapy

Targeting B7‐1 in immunotherapy

Toward Small-Molecule Inhibition of Protein–Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions

High-Affinity Small Molecule Inhibitors of T Cell Costimulation: Compounds for Immunotherapy

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