Humanized Anti-ErbB3 Antibodies for Low-Immunogenic HER3 Blocking
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Solution Overview
Problem
There is a need for improved anti-ErbB3 antibodies that can be used as therapeutic agents to inhibit the activation and overexpression of ErbB3, which is associated with various cancers and resistance to cancer treatments, by preventing ligand binding and dimerization, thereby neutralizing its biological activity.
Innovation Solution
Development of a family of humanized antibodies that specifically bind human ErbB3, containing ErbB3 binding sites based on CDRs, engineered to reduce immune response, and inhibit ErbB3 activation by preventing ligand binding and dimerization, thereby neutralizing its biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-ErbB3 antibodies are used, then ErbB3 binding activity is achieved, but immune response and immunogenicity increase
Solution Approach 1:
The patent applies parameter changes by humanizing the antibody sequences - changing the species origin parameter from murine to human through CDR grafting and framework region substitution. This maintains the binding parameters (affinity, specificity) while changing the immunogenicity parameter to reduce immune response in human patients.
Solution Approach 2:
The patent creates a humanized copy of the murine antibody by transferring the CDR sequences (which contain the binding information) into a human antibody framework. This copying approach preserves the essential binding function while replacing the immunogenic murine framework with a human framework that is less likely to trigger immune responses.
2Productivity
If ErbB3 is overexpressed to drive cancer growth, then tumor proliferation increases, but resistance to cancer treatments develops
Solution Approach 1:
The patent applies preliminary anti-action by using the humanized anti-ErbB3 antibody to pre-emptively block ErbB3 ligand binding and dimerization before cancer cells can activate downstream survival and proliferation pathways. This prevents the constitutive activation that leads to treatment resistance, addressing the problem before it manifests clinically.
Solution Approach 2:
The antibody acts as an intermediary that binds to ErbB3 and prevents direct interaction between ErbB3 and its ligands (such as neuregulin). This intermediary binding blocks the activation signal without requiring degradation of the ErbB3 receptor itself, thereby preventing resistance mechanisms that might arise from receptor overexpression.
3Measurement precision
If murine antibodies are used for therapeutic purposes, then binding specificity is achieved, but human immunogenicity increases
Solution Approach 1:
The patent applies local quality by preserving the CDR regions (which provide binding specificity) while replacing the framework regions with human sequences. This local modification approach maintains the essential binding function in the CDRs while changing the immunogenic framework regions to human-compatible sequences, achieving both specificity and compatibility.
Solution Approach 2:
The humanized antibody is a composite structure combining murine CDR sequences (providing binding specificity) with human framework sequences (providing compatibility). This composite approach integrates the beneficial properties of both murine and human antibody components to achieve both specific binding and reduced immunogenicity.
Data Source
AI summary
Monoclonal antibodies that bind and inhibit activation of epidermal growth factor receptor related member ErbB3/HER3 are disclosed. The antibodies can be used to treat cell proliferative diseases and disorders, including certain forms of cancer, associated with activation of ErbB3/HER3.