Mechanically Interlocked Monoclonal Antibody Complexes
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Solution Overview
Problem
Current methods for enhancing the therapeutic efficacy of monoclonal antibodies by arming them with cytotoxins or radionuclides are limited by available chemistries and require extensive protein engineering, which are inefficient and restrictive.
Innovation Solution
A mechanically interlocked complex is created by attaching a Fab binding moiety to a steric hindering chemical moiety through a chemical linker, where the linker passes through a hole in the Fab domain, establishing a non-covalent bond that enhances binding affinity and allows for the conjugation of therapeutic or diagnostic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are armed with cytotoxins or radionuclides using conventional chemistries, then therapeutic efficacy is enhanced, but extensive protein engineering is required
Solution Approach 1:
The invention divides the antibody into separate Fab domains that can independently bind antigens, while the therapeutic payload is attached to a separate mechanical interlocking component. This segmentation allows the Fab domains to maintain their natural binding capabilities without requiring extensive protein engineering for payload attachment.
Solution Approach 2:
The invention introduces a mechanical interlocking system as an intermediary between the Fab domain and the therapeutic payload. The interlocked complex acts as a mediator that connects the antibody fragment to the payload through a mechanical bond rather than covalent chemistry, eliminating the need for extensive protein engineering while maintaining strong binding.
2Ease of manufacture
If conventional chemistries are used to conjugate therapeutic agents to monoclonal antibodies, then payload delivery is achieved, but the available chemistries are limited and restrictive
Solution Approach 1:
The mechanical interlocking system provides a universal attachment mechanism that can accommodate various therapeutic payloads (cytotoxins, radionuclides, imaging agents) without requiring different chemistries. The interlocked complex serves multiple functions: binding the Fab domain, holding the payload, and enabling easy conjugation through mechanical assembly rather than chemical reactions.
3Reliability
If mechanically interlocked complexes are formed through click chemistry, then binding affinity is significantly increased, but additional chemical functional groups are required
Solution Approach 1:
The Fab domain is pre-modified with a specific amino acid substitution (I83E) that creates a pre-formed binding pocket for the interlocked complex. This preliminary modification allows the subsequent click chemistry reaction to occur with high affinity without requiring complex additional functional groups on the Fab domain itself, as the binding pocket is already prepared to receive the interlocked payload.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly increases the affinity of monoclonal antibodies for antigens, enabling the conjugation of various agents like cytotoxins and imaging agents, thereby enhancing therapeutic efficacy and imaging capabilities without the need for extensive protein engineering.
Implementation Method 1
steric hindrance occurs between the steric hindering chemical moiety and amino acids lining the hole thereby mechanically interlocking the compound and the Fab
Data Source
AI summary
Provided herein are functionalized monoclonal antibodies (mAbs) including antibody fragments, including those where a Fab-binding molecule (Fab binding moiety) linked to a steric hindering molecule (steric hindering chemical moiety) is mechanically interlocked (e.g., through noncovalent conjugation) with the antibody or antibody fragment. Also provided are compositions that form highly stable and versatile drug delivery and diagnostic compositions.