Tetravalent Antibody-Drug Conjugate Enhancing Antigen Internalization
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) targeting EGFR and HER2 have suboptimal activities, and there is a lack of commercially approved ADCs for EGFR-targeted therapy, with existing ADCs relying on conventional bivalent antibodies, which may not effectively engage and internalize antigens on cancer cells.
Innovation Solution
Development of a tetravalent monoclonal antibody conjugated to a cytotoxic drug via a chemical linker, featuring two long chains and four short chains, each forming antigen-binding fragment domains, to enhance antigen binding and internalization, specifically targeting EGFR, HER2, or c-MET, with the option of cleavable or non-cleavable linkers and various cytotoxic drugs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional bivalent antibodies are used in ADCs, then the structure is simpler and easier to manufacture, but the antigen binding and internalization efficiency is suboptimal
Solution Approach 1:
The antibody is divided into multiple functional segments: two long chains (each containing VH-CH1-Fc-VH-CH1) and four short chains (VL-CL), creating a tetravalent structure with four antigen-binding sites. This segmentation allows simultaneous binding to multiple antigens, enhancing internalization efficiency while maintaining manufacturability through modular assembly
Solution Approach 2:
The invention transitions from bivalent (2 binding sites) to tetravalent (4 binding sites) antibody architecture, adding a dimensional aspect to antigen engagement. The tetravalent structure enables binding to multiple antigens simultaneously, creating a more effective therapeutic approach for EGFR-targeted therapy
2Productivity
If tetravalent antibody structure is adopted, then antigen binding and internalization efficiency is improved, but the manufacturing complexity increases
Solution Approach 1:
The complex tetravalent antibody is segmented into standardized long chains and short chains that can be independently produced and then assembled. This modular approach simplifies manufacturing by allowing separate optimization of each chain's production while maintaining the overall tetravalent functionality
Solution Approach 2:
The long chains contain universal Fc regions that can be paired with different variable regions to create antibodies against various targets (EGFR, HER2, c-MET). This universal backbone approach simplifies manufacturing by using a common platform for multiple therapeutic applications
3Reliability
If conventional bivalent ADCs are used, then the development process is faster and simpler, but the antitumor activity is insufficient
Solution Approach 1:
The invention elevates the antibody from bivalent to tetravalent configuration, adding binding valency dimension to enhance antitumor activity. The four antigen-binding sites enable more effective engagement and internalization of target antigens on cancer cells, providing superior therapeutic efficacy
Solution Approach 2:
The ADC comprises a composite structure combining tetravalent antibody (two long chains + four short chains) with cytotoxic drug molecules linked via chemical linkers. This composite design integrates the targeting capability of the antibody with the cytotoxic effect of the drug, creating a more potent antitumor agent
Data Source
AI summary
An antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, is provided. The ADC includes a tetravalent monoclonal antibody conjugated to a cytotoxic drug by a chemical linker. The monoclonal antibody includes two long chains and four short chains. Each of the long chains includes a first segment and a second segment, the first segment located proximal to the N-terminus of the long chain, and the second segment located proximal to the C-terminus of the long chain. Each of the first segment and second segment pairs with one of the short chains to form an antigen-binding fragment domain, therefore forming four antigen-binding fragment domains having specificity toward the same antigen. Pharmaceutical composition including the ADC and methods of treating diseases using the compositions are also provided.