OX40 Antibody CDR Engineering for T Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current OX40-targeted antibodies for cancer treatment face challenges such as immunosuppressive side effects and limited efficacy in less immunogenic environments, with existing agonist monoclonal antibodies showing limited tumor protection.
Innovation Solution
Development of an OX40-targeted antibody and its antigen-binding fragment with specific binding capabilities to human and cynomolgus monkey OX40, promoting NF-κB activation and T-cell activation, and bispecific antibodies capable of binding to OX40 and tumor-associated antigens to recruit and activate T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If agonist monoclonal antibodies targeting OX40 are used for cancer treatment, then T-cell activation is enhanced, but immunosuppressive side effects and limited efficacy occur
Solution Approach 1:
The patent divides the antibody into separate heavy chain and light chain components, enabling independent optimization of each chain's function. The heavy chain is engineered with specific CDR sequences for enhanced OX40 binding and signaling, while the light chain is optimized for stability and reduced immunogenicity, thereby improving efficacy while minimizing side effects
Solution Approach 2:
The patent modifies key parameters of the antibody structure including CDR amino acid sequences, Fc region glycosylation patterns, and half-life extension mutations to optimize the balance between T-cell activation potency and reduction of immunosuppressive effects. Specific mutations in the Fc region alter ADCP activity to enhance anti-tumor function while reducing off-target immunosuppression
2Adaptability or versatility
If conventional antibodies are used, then broad T-cell activation occurs, but light chain mismatch and heterodimerization issues arise
Solution Approach 1:
The patent employs asymmetric design where the heavy and light chains have distinctly optimized sequences and functions. The heavy chain contains engineered CDR3 sequences for potent OX40 recognition, while the light chain is designed with enhanced stability features and reduced propensity for mispairing, creating an asymmetric structure that prevents heterodimerization
Solution Approach 2:
The patent introduces a linker peptide as an intermediary between the heavy and light chains to ensure proper pairing and prevent mismatch. This intermediary element facilitates correct assembly of the antibody heterodimer while preventing formation of incorrect heterodimers, thereby improving manufacturing precision
Data Source
AI summary
An OX40-targeted antibody or an antigen binding fragment thereof. The OX40-targeted antibody comprises a VH. The VH comprises the following CDRs or mutants thereof: a VH CDR1 as shown in an amino acid sequence of SEQ ID NO: 10, a VH CDR2 as shown in an amino acid sequence of SEQ ID NO: 44, and/or a VH CDR3 as shown in an amino acid sequence of SEQ ID NO: 86, SEQ ID NO: 84, or SEQ ID NO: 89. Also disclosed is a preparation method, an application, and a double-antibody comprising same. The antibody or the antigen binding fragment thereof can specifically bind to OX40, promote larger activation of NF-Kb, activate OX40 pathways in vitro, and induce activation of T cell function. The double-antibody can identify tumor target TAA, can bind to OX40 on the T cell, and can recruit and activate T cells near tumor cells to kill tumor cells.