Oral TNF Binders via Engineered Bacterial Carriers
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Solution Overview
Problem
Current anti-TNF-α agents for treating inflammatory bowel diseases have short serum half-lives, requiring frequent injections and leading to immunosuppression-related side effects and poor patient compliance, with oral administration hindered by degradation in the gastrointestinal tract.
Innovation Solution
Development of improved TNF binders, specifically anti-TNF immunoglobulin single variable domains (ISVDs) with enhanced stability and reduced binding by pre-existing antibodies, allowing for effective oral administration and access to the intestinal lamina propria, featuring specific amino acid mutations and C-terminal extensions to prevent degradation and interference.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional monoclonal antibodies are administered systemically to treat IBD, then therapeutic efficacy is achieved, but patient compliance deteriorates due to frequent injections and immunosuppression side effects
Solution Approach 1:
The patent uses engineered bacteria (Lactococcus lactis) as intermediaries to deliver the therapeutic antibody fragment to the gut. The bacteria act as a carrier that protects the antibody from degradation, enables oral administration, and provides localized delivery to the intestinal mucosa, thereby improving patient compliance while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs a simplified version of the therapeutic antibody - a single-domain antibody fragment (VHH or nanobody) instead of a full monoclonal antibody. This copied version retains the essential TNF-neutralizing function while being more stable in the gastrointestinal environment and suitable for oral delivery via bacterial carriers
2Ease of operation
If anti-TNF antibodies are administered orally to avoid injection side effects, then patient compliance improves, but therapeutic efficacy deteriorates due to degradation in the gastrointestinal tract
Solution Approach 1:
Engineered Lactococcus lactis bacteria serve as protective carriers that shield the antibody fragment from gastrointestinal degradation. The bacterial cell structure and intracellular environment protect the therapeutic protein from proteases and acidic conditions, enabling oral administration while preserving biological activity
Solution Approach 2:
The patent modifies the physical and chemical parameters of the antibody by using a single-domain VHH fragment instead of a full antibody. This structural change increases stability against proteolytic degradation and thermal denaturation, making the therapeutic agent suitable for oral delivery through bacterial carriers
3Reliability
If full monoclonal antibodies are used to treat IBD, then therapeutic efficacy is maintained, but manufacturing complexity increases due to production requirements
Solution Approach 1:
The patent extracts only the essential antigen-binding and therapeutic function from the full monoclonal antibody by using a single-variable-domain antibody fragment (VHH). This extracted version retains TNF-neutralizing activity while being simpler to produce, more stable, and suitable for oral delivery via bacterial carriers
Solution Approach 2:
The patent changes the structural parameters of the antibody by employing a camelid-derived single-domain VHH fragment. This structural simplification maintains therapeutic efficacy against TNF while improving stability, reducing manufacturing complexity, and enabling novel delivery routes through engineered bacterial carriers
Data Source
AI summary
The present invention relates to amino acid sequences, compounds and polypeptides binding to tumor necrosis factor alpha (“TNF” or “TNF-alpha”). In particular, the present invention relates to improved heavy-chain immunoglobulin single variable domains (also referred to herein as “ISV's” or “ISVDs”) binding to tumor necrosis factor alpha, as well as to proteins, polypeptides and other constructs, compounds, molecules or chemical entities that comprise such ISVDs, collectively TNF binders. Other aspects, embodiments, features, uses and advantages of the invention will be clear to the skilled person based on the disclosure herein.