ADAM9 Binding Molecules With Cross-Species Affinity and Low Immunogenicity
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Solution Overview
Problem
There is a need for high affinity ADAM9-binding molecules that exhibit minimal binding to normal tissues and can bind to both human and non-human ADAM9 with similar affinity, and improved therapeutics for cancer.
Innovation Solution
Development of monospecific and multispecific binding molecules, including antibodies and diabodies, that are capable of high affinity binding to human and non-human ADAM9, with reduced immunogenicity, utilizing optimized Variable Domains and CDR sequences to enhance binding and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional antibodies are used to target ADAM9, then binding affinity to human ADAM9 can be achieved, but binding affinity to non-human ADAM9 (e.g., cynomolgus monkey) is significantly reduced
Solution Approach 1:
The patent applies parameter changes by optimizing the CDR sequences of the antibody to alter their binding characteristics. Specifically, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 sequences were engineered with specific amino acid compositions and lengths to enhance binding affinity to both human and non-human ADAM9 while maintaining selectivity. This sequence optimization enables the antibody to adapt to slight structural variations in ADAM9 across species.
2Reliability
If high affinity binding to ADAM9 is achieved, then therapeutic efficacy is improved, but immunogenicity of the antibody increases
Solution Approach 1:
The patent applies local quality by humanizing only the variable domains (VH and VL) of the antibody while maintaining the constant regions from murine origin. Specifically, the framework regions of the variable domains were replaced with human sequences, while the CDR regions were optimized for ADAM9 binding. This localized humanization reduces immunogenicity in the regions most likely to trigger immune responses, while preserving the therapeutic function in the CDR regions that bind to the target antigen.
3Measurement precision
If antibody sequences are optimized for human ADAM9 binding, then binding specificity is improved, but binding affinity to non-human ADAM9 decreases
Solution Approach 1:
The patent applies universality by designing CDR sequences that recognize conserved epitopes in ADAM9 across different species. The optimized CDR H1 (12-16 amino acids), CDR H2 (10-14 amino acids), and CDR H3 (13-17 amino acids) sequences were engineered to bind to regions of ADAM9 that are highly conserved between human and non-human species, enabling the antibody to perform multiple functions: maintaining high specificity for human ADAM9 while also binding to non-human ADAM9 with comparable affinity.
Data Source
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AI summary
The present invention is directed to molecules, such as monospecific antibodies and bispecific, trispecific or multispecific binding molecules, including diabodies, BiTEs, and antibodies that are capable of specifically binding to "Disintegrin and Metalloproteinase Domain-containing Protein 9" ("ADAM9"). The invention particularly concerns such binding molecules that are capable of exhibiting high affinity binding to human and non- human ADAM9. The invention further particularly relates to such molecules that are thereby cross-reactive with human ADAM9 and the ADAM9 of a non-human primate (e.g., a cynomolgus monkey). The invention additionally pertains to all such ADAM9-binding molecules that comprise a Light Chain Variable (VL) Domain and/or a Heavy Chain Variable (VH) Domain that has been humanized and/or deimmunized so as to exhibit reduced immunogenicity upon administration of such ADAM9-binding molecule to a recipient subject. The invention is also directed to pharmaceutical compositions that contain any of such ADAM9-binding molecules, and to methods involving the use of any of such ADAM9-binding molecules in the treatment of cancer and other diseases and conditions.