His lab resolved a major controversy by demonstrating that CTLA-4 inhibits T-cell activation by opposing CD28-mediated costimulation
and that blockade of CTLA-4 could enhance T-cell responses, leading to tumor rejection in animal models.
The second, ALPN-202 for cancer, is a dual PD-L1/CTLA-4 antagonist and PD-L1-dependent CD28 costimulator intended to combine checkpoint inhibition with T cell costimulation
an approach currently absent from approved checkpoint therapies.
"CDX-527 joins two powerful pathways in the immune system, PD-1 blockade and CD27 costimulation
. The data we presented at AACR demonstrate that this bispecific antibody candidate has greater activity than the combination of the two individual antibodies and support advancing the program into IND-enabling studies.
(2) This receptor binds to the ligands of a costimulatory marker critical for T cell activation at high affinity, out-competing their binding and thereby preventing delivery of the positive costimulation
signal while preventing activation through delivery of an inhibitory signal through CTLA-4 itself.
CD28/ B7 system of T cell costimulation
. Annu Rev Immunol 1996; 14: 233-58.
via CD80, 4-1BB, and CD83 ligand elicits the long-term growth of V[gamma]9V[delta]2 T cells in low levels of IL-2.
This portfolio of programs targeting immune stimulation, immune checkpoint inhibition, and regulatory T cell function includes ASP8374/PTZ-201, an anti-TIGIT antibody (immune checkpoint inhibitor) and ASP1948/PTZ-329, an anti-NRP1 antibody (Treg function inhibitor), both of which are currently in Phase 1 clinical studies and ASP1951/PTZ-522, a novel format GITR agonistic antibody (T cell priming & costimulation
), which has recently achieved IND clearance.
of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2.
One of the key activating factors is the recognition of certain antigens on the surface of the antigen presenting cells (APC) that provide the necessary costimulation
of T lymphocytes by providing a costimulatory signal.
In the pivotal double-blind, phase 3 trial involving 424 psoriatic arthritis patients, roughly 60% with prior exposure to a tumor necrosis factor inhibitor and 60% on concomitant methotrexate, the proportion of patients with at least 20% improvement in the American College of Rheumatology criteria (ACR20) was 39.4% in patients on the selective T-cell costimulation
modulator, compared with 22.3% among placebo-treated controls.
Under conditions of suboptimal costimulation
, low level expression of CTLA4 could inhibit activation of the T cell, either by directly competing with CD28 for ligand binding and/or by generating inhibitory signals.
Schmitz et al., "Costimulation
via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells," Nature Immunology, vol.