Mesothelin-Targeting Immunoconjugates for Solid Tumor Therapy
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Solution Overview
Problem
Current antibody-based therapies for cancer, particularly targeting mesothelin-expressing cells, face challenges such as low affinity and poor internalization rates, limiting their effectiveness in treating cancers like ovarian, pancreatic, and lung cancer.
Innovation Solution
Development of immunoconjugates comprising antibodies or antibody fragments specifically binding to the 40 kDa C-terminal extracellular part of mesothelin, conjugated with cytotoxic agents like maytansinoids, which can effectively target and kill mesothelin-expressing cancer cells while avoiding competition with cancer antigen 125.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Mab K1 antibody is used to target mesothelin, then the antibody can bind to mesothelin-expressing cancer cells, but the affinity is low and internalization rate is poor
Solution Approach 1:
The patent changes the antibody structure from full IgG format to single-chain Fv (scFv) format, which fundamentally alters the molecular parameters including size, flexibility, and cellular uptake characteristics. This structural parameter change enables improved internalization rates while maintaining mesothelin binding capability
Solution Approach 2:
The patent creates a composite construct by fusing the scFv antibody fragment with a toxin molecule (PE38) to form an immunotoxin. This composite structure combines the targeting capability of the antibody with the cytotoxic activity of the toxin, achieving both high affinity binding and effective cell killing
2Reliability
If SS1-(dsFv)-PE38 immunotoxin is developed to improve killing activity, then tumor cell killing activity increases, but blood clearance becomes fast
Solution Approach 1:
The patent modifies the molecular weight parameter of the immunotoxin by fusing scFv with PE38 toxin, creating a larger complex that slows renal clearance and extends blood circulation time compared to smaller antibody fragments alone
Solution Approach 2:
The patent uses a single-chain Fv fragment instead of a full antibody, which is a smaller, more transient structure that can be rapidly synthesized and degraded, allowing for quick turnover and reduced immunogenicity while maintaining functional activity
3Duration of action of moving object
If pegylation is applied to increase molecular weight, then blood clearance time increases, but the complexity of the molecule increases
Solution Approach 1:
The patent creates a composite immunotoxin structure by fusing the scFv antibody fragment with the PE38 toxin molecule, forming a stable heterodimeric complex. This natural composite structure increases molecular weight and extends circulation time without requiring additional chemical modifications like pegylation
Data Source
AI summary
The present invention provides immunoconjugates composed of antibodies, e.g., monoclonal antibodies, or antibody fragments that bind to mesothelin, that are conjugated to cytotoxic agents, e.g., maytansine, or derivatives thereof, and/or co-administered or formulated with one or more additional anti-cancer agents. The immunoconjugates of the invention can be used in the methods of the invention to treat and/or diagnose and/or monitor cancers, e.g. solid tumors, recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the membrane-anchored, 40 kDa mesothelin polypeptide, which is overexpressed in several tumors, such as pancreatic and ovarian tumors, mesothelioma and lung cancer cells.