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2021-03-09| R&D

Researchers Design Novel Bispecific Antibodies to Nab “Hard-to-Target” Cancer Drivers

by Sahana Shankar
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A lot of our understanding of cancer and tumor progression comes from the studies of tumor suppressor genes such as p53 and RAS, which are known to go rogue/turned off in cancer cells due to mutations. Since these proteins are intracellular and hence inaccessible to antibodies, they are not an attractive target choice for designing specific drugs against them. In a series of studies published in Science, Science Immunology, and Science Translational Medicine, a team of investigators from Johns Hopkins University reports the design of novel bispecific antibodies which recognizes mutant p53, mutant RAS, and T cell receptor (TCRβ) that can be used to develop novel immunotherapeutic interventions.

Immunotherapy aims to recruit the patient’s own immune system to infiltrate the tumor and specifically attack cancer cells based on cancer-specific neoantigens. TCBs (T-cell bispecific antibodies) bring cancer cells in proximity to T cells by simultaneously binding to cancer-specific antigens and T-cell effector recruiting antigens. This allows both tumor homing and recruitment of other immune cells like NK cells or effector T cells to maximize immune response.

p53 mutation R175H is the most commonly observed in various cancers and is expressed on the cancer cell surface as a neoantigen in complex with human leukocyte antigen (HLA). Hence, it is an attractive therapeutic target. Since the volume of p53R175H-presenting cells are at a low density, a specific antibody against it is expected to elicit a robust immune response specific to cancer cells.

 

New Approach to Target Usual Suspects

In this study, the authors used p53 mutants to develop cancer-specific TCR-mimic (TCRm) antibodies that recognize these HLA-derived neopeptides presented on the surface of cancer cells. By screening a phage library of TCRm antibody fragments, the authors found H2 that binds only to p53R175H-HLA complex but not to the wildtype p53 and engineered H2 into a TCB. This novel therapeutic molecule could recognize the p53 neoantigen in cancer cell lines to activate T cells and kill cancer cells in vitro.

Additionally, it caused regression of early and late-stage tumors in mice, suggesting it could effectively recognize cancer cells due to the p53R175H-HLA and mount an effective cytokine storm to kill the cancer cells in vivo. Structural analysis of the H2 with p53R175H-HLA neoantigen showed that H2 envelopes the mutant His175 and showed no cross-reactivity with variant p53 and unrelated peptides, which explains the highly specific interaction and lack of interaction with wildtype p53.

In an accompanying study in Science Immunology, the team was able to use the same strategy to develop similar bispecific antibodies against RAS neoantigens, indicating that this may be a valid immunotherapeutic strategy to target tumor suppressors. Finally, in the Science Translational Medicine paper, the authors demonstrated that the bispecific antibody approach could kill malignant T cells in mouse models of human T cell leukemia while retaining healthy T cells.

The results from these studies establish that it is possible to (a) use tumor suppressors as a therapeutic target, (b) design mutant-specific therapy, (c) evoke a strong immune response with low-volume antigens, and (d) induce multiple T cell responses for effective anti-tumor activity in vivo.

This form of immunotherapy can have minimal safety and toxicity issues due to the reduced risk of off-target effects. Possible limitations of small molecules such as H2 would be rapid clearance from the blood, requiring frequent doses and optimizing antibody design to improve its half-life inside the body, and matching the bispecific antibodies to each patient’s immune system. However, the study provides a blueprint to discover new drug targets and opens a new therapeutic avenue for a broad range of protein-based immunotherapy for cancer.

Related Article: Interferon-γ Pathway Helps Cancer Cells Evade Immune Therapy

References

  1. https://science.sciencemag.org/content/371/6533/eabc8697
  2. https://immunology.sciencemag.org/content/6/57/eabd5515
  3. https://stm.sciencemag.org/content/early/2021/02/22/scitranslmed.abd3595
  4. https://science.sciencemag.org/content/371/6533/996

 

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