Humanized Nectin-4 ADC Antibodies With Lower Immunogenicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is an unmet need for humanized antibodies that specifically recognize human Nectin-4 and antibody-drug conjugates (ADCs) that are safe, potent, and effective in treating cancers expressing Nectin-4, as existing murine-origin antibodies are less suitable for clinical use and current ADCs like PADCEV have limitations.
Innovation Solution
Development of humanized antibodies with modified variable regions and specific mutations, combined with cytotoxic moieties, to enhance binding affinity and minimize immune response, while reducing aggregation and FcγR-mediated interactions, resulting in improved ADCs like NTX1105 that demonstrate superior anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine-origin antibodies are used against Nectin-4, then binding affinity to Nectin-4 can be achieved, but immunogenicity increases and suitability for clinical use decreases
Solution Approach 1:
The patent applies humanization by changing the amino acid sequence parameters of the antibody variable regions. Specifically, it replaces murine framework regions with human framework regions while retaining the CDR sequences, thereby changing the immunogenicity parameter while preserving Nectin-4 binding affinity. This is evidenced by the sequential development from chimeric (25% human) to humanized (90-95% human) antibodies.
Solution Approach 2:
The patent segments the antibody structure into functional regions with different origins: CDR sequences from murine antibodies are retained for antigen binding, while framework regions are replaced with human sequences to reduce immunogenicity. This segmentation allows independent optimization of binding affinity and immunogenicity properties.
2Reliability
If standard ADC designs are used with anti-Nectin-4 antibodies, then tumor targeting is achieved, but systemic toxicity remains high
Solution Approach 1:
The patent applies local quality optimization by modifying specific regions of the antibody molecule. The Fc region is engineered with specific amino acid substitutions (e.g., L234A/L235A in IgG1) that locally alter FcγR binding properties without affecting the antigen-binding CDR regions. This allows selective modification of effector function while maintaining tumor targeting capability.
Solution Approach 2:
The patent introduces linker molecules as intermediaries between the antibody and cytotoxic payload. These linkers (e.g., MC-VC-PAB, SMCC) are designed to remain stable in circulation (reducing systemic toxicity) while being cleavable in the tumor microenvironment or endosomes, enabling controlled payload release only at the target site.
3Reliability
If existing ADCs like PADCEV are used, then some anti-tumor activity is achieved, but efficacy is insufficient in certain treatment regimens
Solution Approach 1:
The patent creates composite ADC structures combining humanized anti-Nectin-4 antibodies with optimized linkers and cytotoxic payloads (MMAE, MMAF, DM1, DM4). This composite approach allows synergistic optimization: the humanized antibody provides improved pharmacokinetics and reduced immunogenicity, while the optimized payload-linker-antibody combination enhances cellular internalization and cytotoxic efficacy.
Solution Approach 2:
The patent systematically varies key ADC parameters including drug-to-antibody ratio (DAR), linker chemistry, and payload type to optimize therapeutic efficacy. By changing these parameters and evaluating their impact on in vitro and in vivo performance, the patent identifies optimal combinations that overcome the limitations of existing ADCs like PADCEV.
Data Source
AI summary
The present invention provides humanized antibodies against Nectin-4 and antibody drug conjugates (ADCs) of the humanized antibodies and use thereof in treating diseases, in particular cancer.