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Updated: Oct 2, 2025
Generation of Discriminative Human Monoclonal Antibodies from Rare Antigen-specific B Cells Circulating in Blood
Published on: February 6, 2018
Engineering Antibodies Targeting p16 MHC-Peptide Complexes
Nicholas J Rettko1, Judith Campisi2,3, James A Wells1,4
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States.
Abstract:
Senescent cells undergo a permanent cell cycle arrest and drive a host of age-related pathologies. Recent transgenic mouse models indicate that removing cells expressing the senescence marker p16Ink4a (p16) can increase median lifespan and delay the onset of many aging phenotypes. However, identifying and eliminating native human cells expressing p16 has remained a challenge. We hypothesize that senescent cells display peptides derived from p16 in major histocompatibility complex (MHC)-peptide complexes on the cell surface that could serve as targetable antigens for antibody-based biologics. Using Fab-phage display technology, we generated antibodies that bind to a p16 MHC-peptide complex from the human leukocyte antigen (HLA) allele HLA-B*35:01. When converted to single-chain Fab chimeric antigen receptor (CAR) constructs, these antibodies can recognize naturally presented p16 MHC-peptide complexes on the surface of cells and activate Jurkat cells. Furthermore, we developed antibodies against predicted p16 MHC-peptide complexes for HLA-A*02:01 that specifically recognize their respective antigen on the surface of cells. These tools establish a platform to survey the surface of senescent cells and provide a potential novel senolytic strategy.
Insights
Researchers identified a novel way to target senescent cells, which contribute to aging. They developed antibodies that recognize a specific protein (p16) on these cells, offering a potential new strategy for senolytic therapies.
Area of Science:
- Immunology
- Cell Biology
- Gerontology
Background:
- Senescent cells permanently arrest cell division and contribute to age-related diseases.
- Eliminating senescent cells expressing p16Ink4a (p16) in mice increases lifespan and delays aging.
- Targeting native human senescent cells expressing p16 remains a significant challenge.
Purpose of the Study:
- To investigate if senescent cells display p16-derived peptides in major histocompatibility complex (MHC)-peptide complexes on their surface.
- To develop antibody-based biologics targeting these unique cell surface antigens for senolytic therapy.
Main Methods:
- Utilized Fab-phage display technology to generate antibodies against p16 MHC-peptide complexes.
- Created antibodies targeting p16 MHC-peptide complexes associated with HLA-B*35:01 and HLA-A*02:01 alleles.
- Engineered single-chain Fab chimeric antigen receptor (CAR) constructs from generated antibodies.
Main Results:
- Successfully generated antibodies that bind to p16 MHC-peptide complexes on specific human leukocyte antigen (HLA) alleles.
- Demonstrated that CAR constructs can recognize naturally presented p16 MHC-peptide complexes on target cells.
- Showed activation of Jurkat cells upon recognition of these senescent cell surface antigens.
Conclusions:
- Senescent cells present p16-derived peptides within MHC-peptide complexes on their surface, serving as potential targetable antigens.
- Developed a platform for surveying senescent cells using novel antibodies.
- Established a potential new senolytic strategy targeting p16-expressing senescent cells via antibody-based biologics.
