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Physicochemical developability insights into human Fab fragments with extended hypervariable loops
Marcel Passon1, Gianluca Bandera2, Leonard Mayerhöfer2
1Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium; Biopharmaceutical Technology, TUM School of Life Sciences, Technical University of Munich, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany.
Journal of Pharmaceutical Sciences
|July 31, 2026
Summary
Human antibodies with extended complementarity-determining regions (CDRs) offer therapeutic potential but face developability challenges. Analysis reveals sequence-dependent features, not just length, influence antibody liabilities, guiding development strategies.
Area of Science:
- Biochemistry
- Immunology
- Pharmaceutical Science
Background:
- Human antibodies with extended complementarity-determining regions (CDRs) present unique therapeutic opportunities for targeting challenging molecules.
- However, the developability of these antibodies for pharmaceutical applications can be hindered by potential issues.
Purpose of the Study:
- To analyze the developability of human antibody fragments (Fabs) with extended CDR-H3s.
- To identify sequence-dependent features and liabilities associated with long CDR-H3s.
- To inform mechanistically guided strategies for antibody drug development.
Main Methods:
- Integrated experimental and computational workflows were employed.
- Five human Fabs with long CDR-H3s were assessed for secretion, homogeneity, conformational and colloidal stability, and non-specific binding.
- Molecular dynamics simulations were used to probe conformational dynamics and interpret experimental findings.
Main Results:
- Extended CDR-H3s exhibit general sequence-dependent characteristics and liabilities.
- These features are not solely determined by the length of the CDR-H3.
- Experimental and computational analyses provided insights into the underlying mechanisms.
Conclusions:
- Developability of human antibodies with extended CDR-H3s is influenced by specific amino acid sequences.
- A mechanistically informed development strategy is crucial for optimizing these therapeutic candidates.
- This research aids in overcoming challenges in developing antibodies with enhanced binding capabilities.
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