Related Experiment Video
Updated: Jul 15, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Conditionally Active, pH-Sensitive Immunoregulatory Antibodies Targeting VISTA and CTLA-4 Lead an Emerging Class of
F Donelson Smith1, Robert H Pierce2, Thomas Thisted1
1Sensei Biotherapeutics, Inc., 1405 Research Blvd., Suite 125, Rockville, MD 20850, USA.
Abstract:
Immune checkpoints and other immunoregulatory targets can be difficult to precisely target due to expression on non-tumor immune cells critical to maintaining immune homeostasis in healthy tissues. On-target/off-tumor binding of therapeutics results in significant pharmacokinetic and pharmacodynamic problems. Target-mediated drug disposition (TMDD) significantly limits effective intratumoral drug levels and adversely affects anti-tumor efficacy. Target engagement outside the tumor environment may lead to severe immune-related adverse events (irAEs), resulting in a narrowing of the therapeutic window, sub-optimal dosing, or cessation of drug development altogether. Overcoming these challenges has become tractable through recent advances in antibody engineering and screening approaches. Here, we review the discovery and development of conditionally active antibodies with minimal binding to target at physiologic pH but high-affinity target binding at the low pH of the tumor microenvironment by focusing on the discovery and improved properties of pH-dependent mAbs targeting two T cell checkpoints, VISTA and CTLA-4.
Insights
Conditionally active antibodies target tumor microenvironments by binding at low pH, improving T cell checkpoint therapy. This approach minimizes off-tumor binding, reducing adverse events and enhancing anti-tumor efficacy.
Area of Science:
- Immunology and Cancer Therapeutics
- Antibody Engineering
Background:
- Immune checkpoints and immunoregulatory targets are difficult to precisely target due to expression on vital non-tumor immune cells, impacting immune homeostasis.
- On-target/off-tumor binding of therapeutics causes pharmacokinetic/pharmacodynamic issues, limiting intratumoral drug levels and anti-tumor efficacy via Target-Mediated Drug Disposition (TMDD).
- Off-tumor target engagement can lead to severe immune-related adverse events (irAEs), narrowing the therapeutic window and hindering drug development.
Purpose of the Study:
- To review the discovery and development of conditionally active antibodies for improved cancer immunotherapy.
- To highlight pH-dependent monoclonal antibodies (mAbs) that exhibit minimal target binding at physiologic pH but high-affinity binding in the acidic tumor microenvironment.
- To focus on novel pH-dependent mAbs targeting the T cell checkpoints VISTA and CTLA-4.
Main Methods:
- Review of recent advances in antibody engineering and screening approaches.
- Focus on the discovery and improved properties of pH-dependent monoclonal antibodies (mAbs).
- Development of antibodies with differential target binding based on pH variations between healthy tissue and the tumor microenvironment.
Main Results:
- Development of conditionally active antibodies with minimal binding to target at physiologic pH.
- Achieved high-affinity target binding specifically at the low pH characteristic of the tumor microenvironment.
- Improved properties of pH-dependent mAbs targeting VISTA and CTLA-4.
Conclusions:
- Advances in antibody engineering enable the development of therapeutics with enhanced tumor specificity.
- pH-dependent antibodies offer a strategy to overcome challenges associated with on-target/off-tumor binding and irAEs.
- Conditionally active antibodies targeting VISTA and CTLA-4 show promise for improving anti-tumor efficacy and therapeutic windows in cancer treatment.
Related Concept Videos
01:27Tumor Immunotherapy
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:30Cancer Vaccines
Cancer vaccines come in two categories: preventive (prophylactic) and treatment (active). Preventive vaccines, such as the Human Papillomavirus (HPV) vaccine, protect against viruses that cause certain...
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...