Costimulatory Molecules Development

In T cell signaling, at least two signals are considered integral in defining the fate of naive T cells and their competence to combat disease. Major histocompatibility complex (MHC)-peptide interactions with T cell receptor (TCR) provide the first signal in immune responses. However, while the MHC–peptide interaction with TCR is essential in determining specificity and initiating T cell activation, this process is not sufficient to determine the fate of T cells. Costimulatory and coinhibitory molecules, which are cell surface glycoprotein molecules, supply additional signal or “second signal” to T cells through antigen-presenting cells (APCs), providing context to the state of activation or inactivation that develops within the T cell. The second signal delivered is most likely a product of both costimulatory and coinhibitory influences. Positive signals result in T cell proliferation, expansion, and survival; specific cytokine release; and cytotoxic effector responses. Negative signaling results in T cell death, reduced memory responses, suppressor T cell induction, and immunosuppressive cytokine secretion.

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B7/CD28/CTLA4 Pathway

An example of a signaling system with both positive and negative output is the B7/CD28/CTLA4 pathway, the most thoroughly studied cosignaling pathway. CD28 ligation on T cells results in costimulatory signals delivered by B7-1 (CD80) and B7-2 (CD86). CTLA4 provides coinhibitory signals also through interactions with B7-1 and B7-2. CTLA4-deficient mice exhibit severe lymphoproliferative disease and autoimmunity. Considering the range of immune responses that can be elicited by these molecules, it is not surprising that tumor cells have enlisted costimulatory/coinhibitory molecule to help in their armamentarium to render them poorly immunogenic or nonimmunogenic.

The influence of costimulatory/coinhibitory molecules on the state of T cell activation and their expression on cancer cells has made these molecules attractive agents for immunotherapy. While anti-CTLA4 antibody therapy is the first in this class of tumor immunotherapy to reach clinical trials and exhibit efficacy, its association with the development of grade 3/4 autoimmunity supports investigation into the therapeutic potential of other costimulatory/coinhibitory molecules, as they may grade the potency of the immune response on a different contextual scale. The molecules that are currently being brought to phase I clinical trials for therapeutic applicability are members of the PD-1/B7-H1/B7-DC pathway and the CD137/CD137L pathway. Each has been shown in various model systems to influence and enhance productive antitumor immune responses.

PD-1/B7-H1/B7-DC Pathway

Immunotherapeutic strategies aimed at manipulating the PD-1/B7-H1/B7-DC pathway have the capacity to not only rejuvenate T cells but also push T cells into an activated state when other forms of “help” cannot be provided.

CD137 and CD137 Ligand

Signaling systems such as the CD137: CD137L pathway may improve the antitumor response by augmenting not only selective responses but also responses in low-antigen-level states.

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