PD1 and LAG3 Binders Engineered to Reduce Pre-Existing Antibody Binding
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Solution Overview
Problem
Existing therapies targeting the PD-1/PD-L1 pathway for cancer and infectious diseases face challenges due to immune tolerance and exhaustion of tumor-specific CD8+ T cells, which hinder effective immune responses.
Innovation Solution
Development of PD1 and LAG3 binders, such as ISVDs and Nanobodies, engineered to reduce pre-existing antibody binding and enhance immune response by blocking the interaction between PD-1 and its ligands, thereby activating T cells and boosting anti-tumor and anti-infective immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1/PD-L1 pathway is blocked to enhance T-cell immunity, then tumor-specific CD8+ T-cell immunity is enhanced, but immune tolerance and exhaustion prevent effective immune responses
Solution Approach 1:
The invention segments the immune checkpoint blockade strategy by targeting multiple pathways simultaneously - combining PD-1 blockade with LAG-3 blockade - to overcome the limitations of single-pathway inhibition and address immune tolerance through multi-dimensional intervention
Solution Approach 2:
The invention uses composite therapeutic approach by creating bispecific antibodies or antibody combinations that simultaneously target both PD-1 and LAG-3 pathways, effectively creating a composite immune activation strategy that overcomes the harmful effects of immune tolerance and exhaustion
2Reliability
If conventional antibody therapies are used to target PD-1, then PD-1 binding is achieved, but pre-existing human antibodies reduce therapeutic efficacy
Solution Approach 1:
The invention changes the structural parameters of the antibody by using camelid-derived single-domain antibodies (VHH) with fundamentally different structural characteristics compared to conventional mammalian antibodies, thereby avoiding recognition by pre-existing human anti-human antibodies while maintaining PD-1 binding capability
Solution Approach 2:
The invention employs simplified single-domain antibody structures that are more resilient and can be rapidly produced, serving as effective therapeutic agents that are not neutralized by pre-existing antibodies, effectively replacing conventional antibodies that suffer from immunogenicity issues
Data Source
AI summary
The present invention provides molecules, such as ISVDs and Nanobodies, that bind to PD1 and LAG3 and, optionally to human serum albumin. These molecules have been engineered so as to reduce the incidence of binding by pre-existing antibodies in the bodies of a subject administered such a molecule. Methods for increasing immune response, treating cancer and/or treating an infectious disease with such molecules are provided.