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Tumor Immunotherapy

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.

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Updated: May 31, 2025

Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses

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Engineered ipilimumab variants that bind human and mouse CTLA-4.

Brett Robison¹, S J Diong¹, Anusha Kumar¹

¹Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, CA, USA.

|January 24, 2025

Summary

This summary is machine-generated.

Developing better mouse models for cancer immunotherapy is crucial. This study engineered an antibody to bind both human and mouse CTLA-4, improving preclinical cancer research translatability.

Keywords:

Antibody engineering CTLA-4 immune checkpoint phage display species cross reactivity yeast display

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Published on: February 6, 2017

Area of Science:

Immunology
Biochemistry
Drug Development

Background:

Preclinical models are essential for antibody therapeutic development.
Surrogate antibodies are often needed for mouse models, but can present challenges.
The antibody 9D9 is a common surrogate for mouse CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) studies.

Purpose of the Study:

To investigate the biophysical properties of the 9D9 surrogate antibody.
To engineer an antibody with improved binding to mouse CTLA-4 for better preclinical models.
To enhance the translatability of anti-CTLA-4 cancer therapies.

Main Methods:

Determined the crystal structure of the 9D9-mouse CTLA-4 complex.
Utilized phage and yeast display to engineer ipilimumab variants.
Determined crystal structures of engineered variants complexed with mouse and human CTLA-4.

Main Results:

The 9D9 antibody binds a distinct epitope from therapeutic antibodies and exhibits pH-dependent binding.
Engineered ipilimumab variants demonstrated single-digit nM affinity for mouse CTLA-4.
Engineered variants showed pH-independent, cross-reactive binding to both mouse and human CTLA-4 at the same epitope as ipilimumab.

Conclusions:

The 9D9 surrogate antibody has significant biophysical differences compared to therapeutic CTLA-4 antibodies.
Engineered ipilimumab variants offer improved cross-reactivity and pH-independent binding.
These variants may enhance the translatability of anti-CTLA-4 therapies and facilitate mechanism-of-action studies in murine models.