Variant PD-L1 Polypeptides for Selective T Cell Modulation
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Solution Overview
Problem
Current immunotherapies face challenges in selectively modulating T cell activity due to the non-epitope specific nature of costimulatory proteins like PD-L1, which affects the specificity and efficacy of T cell activation or inhibition.
Innovation Solution
Development of variant PD-L1 immunomodulatory polypeptides with altered binding affinities to PD-1 and B7-1, allowing for reduced binding to PD-1 while maintaining or enhancing binding to B7-1, thereby modulating T cell activity with improved target cell specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If costimulatory proteins like PD-L1 are used for T cell modulation, then T cell activity can be inhibited or activated, but the lack of epitope specificity reduces the precision of target cell modulation
Solution Approach 1:
The patent applies local quality by creating variant PD-L1 polypeptides with non-uniform binding affinities to different costimulatory proteins. Specifically, the variants have reduced binding affinity to PD-1 while maintaining or enhancing binding affinity to B7-1, allowing selective modulation of T cell subsets based on their respective costimulatory protein dependencies
Solution Approach 2:
The patent utilizes parameter changes by systematically altering the binding affinity parameters of PD-L1 variants to different costimulatory proteins. Through amino acid sequence modifications, the polypeptides achieve differentiated binding characteristics that enable selective T cell modulation, with measured binding affinity changes providing quantitative control over therapeutic effect
2Adaptability or versatility
If wild-type PD-L1 is used to modulate T cells, then broad T cell activity can be inhibited, but the non-epitope specific binding reduces the ability to selectively target specific T cell populations
Solution Approach 1:
The patent applies segmentation by dividing the T cell modulation function into separate pathways targeted by different PD-L1 variants. One variant segment targets PD-1 mediated inhibition while another segment targets B7-1 mediated activation, allowing independent control of different T cell populations
Solution Approach 2:
The patent creates local quality differentiation within the PD-L1 protein structure through amino acid substitutions that locally alter binding affinity to specific costimulatory proteins, enabling the same protein family to exert different functional effects on different T cell subsets
Data Source
AI summary
The present disclosure provides variant PD-L1 immunomodulatory polypeptides, and fusion polypeptides comprising the variant immunomodulatory peptides. The present disclosure provides T-cell modulatory multimeric polypeptides, and compositions comprising same, where the T-cell modulatory multimeric polypeptides comprise a variant immunomodulatory polypeptide of the present disclosure. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the T-cell modulatory multimeric polypeptides, and host cells comprising the nucleic acids. The present disclosure provides methods of modulating the activity of a T cell; the methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide of the present disclosure.