Anti-ROR1 Antibody CDR Optimization for CAR Cell Targeting
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Solution Overview
Problem
There is a need for improved ROR1-binding molecules and engineered ROR1-binding receptor-expressing cells to target ROR1, which is expressed in various cancers and involved in cell signaling to promote tumor cell survival.
Innovation Solution
Development of anti-ROR1 antibodies and chimeric antigen receptors (CARs) with specific CDR sequences that bind to ROR1, along with genetically engineered cells expressing these receptors for use in adoptive cell therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ROR1-binding molecules are used, then ROR1 targeting is achieved, but therapeutic efficacy and tumor cell survival enhancement are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically optimizing the complementarity determining regions (CDRs) of the antibody. Multiple variants of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are disclosed with specific amino acid sequences that enhance binding affinity and therapeutic efficacy while maintaining the overall antibody structure. This allows improvement in therapeutic reliability through precise sequence parameter optimization without requiring complete structural redesign.
2Measurement precision
If ROR1-binding molecules with high specificity are developed, then tumor cell targeting is improved, but the complexity of molecular design and engineering increases
Solution Approach 1:
The patent applies local quality by focusing optimization efforts specifically on the CDR regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3) of the antibody while keeping the framework regions relatively standardized. This allows the molecule to achieve high ROR1 binding specificity through localized sequence variations in the antigen-binding sites without requiring complex changes throughout the entire molecular structure.
Solution Approach 2:
The patent systematically varies specific amino acid parameters in the CDR sequences to optimize ROR1 binding specificity. Multiple disclosed variants show how changing specific residues in CDR-H3 and CDR-L3 regions, in particular, can enhance epitope recognition and binding affinity while maintaining manageable molecular design complexity.
3Adaptability or versatility
If genetically engineered cells expressing ROR1-binding receptors are created, then adoptive cell therapy capability is enhanced, but manufacturing and genetic engineering complexity increases
Solution Approach 1:
The patent applies universality by designing chimeric antigen receptors (CARs) that combine the optimized ROR1-binding antibody variable regions with standardized signaling domains and transmembrane regions. The disclosed CAR constructs can be expressed in various T cell types and other immune cells, providing broad adaptability for adoptive cell therapy while using modular, relatively straightforward genetic engineering approaches that do not require cell-type-specific complex modifications.
Data Source
AI summary
Provided are receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules, in particular, to human antibodies specific for ROR1, including antibody fragments. The present disclosure further relates to recombinant receptors, including chimeric antigen receptors (CARs) that contain such antibodies or fragments, and polynucleotides that encode the antibodies, antigen-binding fragments or receptors specific for ROR1. The disclosure further relates to genetically engineered cells, containing such ROR1-binding proteins and receptors, and related methods and uses thereof in adoptive cell therapy.