PD1 CTLA4 Binders Reduce Pre-existing Antibody Binding
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Solution Overview
Problem
Current methods for blocking the interactions between immune regulatory molecules like CTLA4 and PD1 with Nanobodies may induce unwanted anti-drug immune responses due to pre-existing antibodies, necessitating the development of novel humanized Nanobodies that minimize such reactions.
Innovation Solution
Design and development of multispecific immunoglobulin single variable domains (ISVDs) that bind to human PD1 and CTLA4, specifically targeting residues like VRVTVL, ADSQVTEVC, and CKVELMYPPPYYLG, with mutations at positions 11, 89, and 112 to reduce pre-existing antibody binding, and optionally incorporating peptide linkers and half-life extenders for enhanced stability and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Nanobodies are used to block CTLA4 and PD1 interactions, then immune inhibitory signals are blocked and tumor regression is promoted, but unwanted anti-drug immune responses are induced due to pre-existing antibodies
Solution Approach 1:
The patent applies parameter changes by introducing specific point mutations at positions 11, 89, and 112 in the Nanobody sequence. These mutations alter the binding interface properties to reduce affinity for pre-existing antibodies while maintaining the original antigen-binding function, thereby resolving the contradiction between efficacy and immunogenicity
Solution Approach 2:
The patent creates humanized Nanobodies by copying and adapting the functional framework of llama-derived Nanobodies into a human immunoglobulin scaffold. This involves transferring the critical binding residues while replacing the framework regions with human sequences, reducing immunogenicity while preserving the blocking function against CTLA4 and PD1
2Object-affected harmful factors
If mutations are introduced at positions 11, 89, and 112 to reduce pre-existing antibody binding, then anti-drug immune responses are minimized, but the complexity of the binder sequence increases
Solution Approach 1:
The patent applies local quality by making targeted point mutations only at specific positions (11, 89, and 112) within the Nanobody sequence rather than redesigning the entire molecule. This localized approach reduces pre-existing antibody binding at critical interface regions while leaving the rest of the stable framework unchanged, thus minimizing overall sequence complexity
Data Source
AI summary
The present invention provides multispecific molecules, e.g., comprising more than one ISVD or Nanobody, that bind to PD1 and CTLA4. 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.