Multispecific Antibody Assembly for Site-Specific ADC Payload Positioning
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) face challenges in maintaining antigen binding while ensuring site-specific payload attachment, leading to compromised functionality and complex production processes due to random coupling and variable stoichiometry, which complicates the identification of optimal ADCs.
Innovation Solution
A method utilizing Format Chain Exchange (ForCE) technology to produce polypeptide complexes by incubating precursor complexes with destabilizing CH3 domain modifications, allowing for the formation of stable, payload-bearing molecules with defined matrices of binders and formats through knob-hole interactions, enabling efficient production of ADCs with consistent performance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If site-directed conjugation with mutated residues is used to achieve precise payload attachment, then payload positioning precision is improved, but production complexity increases
Solution Approach 1:
The antibody is divided into separate heavy and light chain precursors that are produced independently and then assembled. This segmentation allows for simplified production of each component while achieving precise payload positioning through controlled assembly of the complete antibody structure.
Solution Approach 2:
The payload is attached to the antibody in advance during the conjugation process before final assembly. This preliminary action ensures precise payload positioning is achieved while avoiding the need for complex post-production modifications, thereby reducing overall production complexity.
2Reliability
If comprehensive ADC matrices are produced to cover design space, then ADC functionality is improved, but production time increases
Solution Approach 1:
The comprehensive ADC matrix is segmented into multiple smaller production batches, each focusing on specific binder-format-payload combinations. This allows parallel production of different ADC variants, maintaining functional comprehensiveness while reducing the time required for each individual production run.
Solution Approach 2:
Instead of producing all possible ADC combinations in a single comprehensive matrix, the approach uses partial action by producing only the most promising combinations identified through preliminary screening. This reduces production time while still achieving sufficient ADC functionality coverage for drug development.
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 enables rapid, reliable generation of defined matrices of ADCs with precise payload positioning and stoichiometry, enhancing the stability and functionality of ADCs by stabilizing associations between CH3 domains, thus improving the production efficiency and consistency of ADCs.
Implementation Method 1
The CH3 domain of the first polypeptide comprises a knob modification, and the CH3 domain of the second polypeptide comprises a hole modification
Implementation Method 2
the CH3 domain of the first polypeptide or the second polypeptide comprises a destabilising modification for destabilising association between the CH3 domain of the first polypeptide and the CH3 domain of the second polypeptide
Data Source
AI summary
The present disclosure relates to a variant of ForCE technology (which is described e.g. in Dengl et al. 2020 and WO 2019/077092 A1), that can be employed for the production of payload-bearing molecules (such as antibody-drug conjugates), through combining functional (e.g. binding) entities with payload-coupled Fc molecules. The principle upon which the present disclosure is based is illustrated in the schematic of FIG. 1.