Characterization and Efficacy Analysis of a Novel Immunotherapy
Abstract/Contents
- Abstract
- In recent decades, cancer immunotherapy has emerged as a potent strategy to promote immune clearance of tumors. Checkpoint blockade, a specific form of cancer immunotherapy that aims to block inhibitory immune checkpoint proteins, has proven to be therapeutic for certain cancers. V-domain Ig Suppressor of T Cell Activation (VISTA) is an immune checkpoint protein that inhibits the T cell response against cancer. Similar to blockade of checkpoint proteins like PD-1 and CTLA-4, VISTA blockade promotes anti-tumor immunity. However, unlike PD-1 and CTLA-4, VISTA is highly expressed as a ligand on antigen-presenting cells (APCs) and other myeloid cells, including myeloid-derived suppressor cells (MDSCs), which are often found in the immunosuppressive tumor microenvironment. While other groups have engineered antibodies against the human VISTA protein, an antibody that can bind tightly to both human and mouse VISTA is not available. An antibody developed by Hummingbird Biosciences, binds to mouse VISTA, but with significantly weaker affinity as compared to human VISTA. Having an antibody that can inhibit both mouse and human VISTA allows for improved clinical translation with fewer unanticipated toxicities when transitioning from preclinical animal models to human clinical testing. Here we characterize the ability of a new species cross-reactive anti-VISTA antibody to inhibit VISTA function. We also compared the molecular interactions of this antibody to other clinically relevant, human-specific anti-VISTA antibodies. Confirmation of our antibody’s ability to inhibit VISTA function was confirmed via in vitro analysis of T cell interaction with VISTA. Furthermore, we show that our anti-VISTA antibody blocks interaction between VISTA and the protein PSGL-1, which is expressed on T cells and thought to mediate VISTA inhibitory signaling. Finally, we demonstrate that our antibody shows therapeutic efficacy in in vivo tumor studies. Thus, we show this species cross-reactive anti-VISTA antibody has therapeutic promise while providing a framework for the development of next-generation cross-reactive anti-VISTA therapies for cancer.
Description
| Type of resource | text |
|---|---|
| Date created | May 2020 |
Creators/Contributors
| Author | Maddineni, Sainiteesh |
|---|---|
| Advisor | Altman, Russ Biagio |
| Principal investigator | Cochran, Jennifer |
Subjects
| Subject | cancer |
|---|---|
| Subject | immunology |
| Subject | immunotherapy |
| Subject | antibody |
| Subject | bioengineering |
| Subject | engineering |
| Genre | Thesis |
Bibliographic information
| Related Publication | Mehta, N., Maddineni, S., Kelly, R.L. et al. An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA. Sci Rep 10, 15171 (2020). https://doi-org.stanford.idm.oclc.org/10.1038/s41598-020-71519-4 |
|---|---|
| Location | https://purl.stanford.edu/vk247mx5194 |
Access conditions
- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Preferred citation
- Preferred Citation
- Maddineni, Sainiteesh. (2020). Characterization and Efficacy Analysis of a Novel Immunotherapy. Stanford Digital Repository. Available at: https://purl.stanford.edu/vk247mx5194
Collection
Undergraduate Theses, School of Engineering
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- Contact
- smaddineni@stanford.edu
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