Manipulation of the immune response with either antagonistic antibodies of immune-repressor molecules or agonistic antibodies of immune-activating receptors has found great potential in the application for immune disease, cancer, and infectious disease therapy. While the antagonistic antibodies dominate the immune-checkpoint antibody drug discovery field, agonistic antibodies represent promising agents and various studies have reported antibody development targeting costimulatory molecules, such as CD27, CD40, OX40, 4‑1BB, GITR, ICOS, and CD28. Here, Creative Biolabs gives a brief introduction to the therapeutic application of agonistic antibodies in different diseases.
Cancers can co-opt the immune-checkpoint pathways to evade the immune system. However, the discovery of the fact that therapeutic antibodies that block these receptors can take the brakes off the anti-tumor immune response and stimulate antitumor immunity, contributing to the development of immune-checkpoint antibodies. Antagonistic antibodies targeting coinhibitory receptors, such as CTLA-4 and PD-1, have been approved as monotherapies for advanced melanoma, lung cancer, and evaluated for the treatment of other types of human cancers.
Besides targeting the inhibitory pathways, agonist antibodies directed against the immunostimulatory receptors can also stimulate antitumor immunity and are emerging as a promising area of clinical development for cancer immunotherapies. For instance, Vonderheide et al. (2013) reviewed the use of agonistic CD40 monoclonal antibodies (mAbs) for cancer therapy, which has shown highly promising results without disabling toxicity. This CD40 mAb can activate antigen-presenting cells (APCs), promote antitumor T-cell responses, and foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity.
Fig.1 Potential mechanisms of action of agonistic CD40 mAb on various immune effectors. (Vonderheide, 2013)
Immune-checkpoint receptors play a crucial role in immune regulatory function and studies have reported defects of immune-checkpoint has been associated with a number of diseases. This raised the possibility that inducing signaling through these receptors could switch off detrimental immune responses and drive the immune system back toward a state of tolerance after control has versus in autoimmune disease. As a result, a range of different targeted has been explored for both antagonistic and agonistic antibody drug development for the treatment of diseases including rheumatoid arthritis, systemic sclerosis, graft-versus-host disease (GVHD), autoimmune uveitis, lupus nephritis, etc.
Due to the complexity of the tumor microenvironment, many cancers fail to respond to single-agent immune checkpoint antibody therapies. As a result, combinations of immune-checkpoint therapies with other treatment modalities (e.g., surgery, chemotherapy, and radiation), immune-checkpoint therapies (e.g., agonist antibody with antagonist antibody), as well as evidence types of immunotherapeutic strategies (e.g., cytokine therapy, chimeric antigen receptor (CAR) T cells, tumor vaccines, oncolytic viral therapies) have been explored. Combination therapies often result in increased immune cell infiltration and a more significant decrease of tumors.
Fig.2 Schematic representation of the combined effects of agonistic anti-CD40 mAb treatment and sunitinib or individual monotherapies in the tumor and tumor-draining lymph node. (van Hooren, 2016)
Specialized in agonistic antibody development, Creative Biolabs offers the following services to global clients:
Creative Biolabs has accumulated abundant experience with the successful discovery of agonist antibodies to a panel of receptors. We are happy to assist you with your brilliant studies and projects. For more detailed information, please feel free to contact us or directly send us an online inquiry.