Engineering fully human monoclonal antibodies from murine variable regions.

Area of Science:

• Biotechnology
• Immunology
• Drug Development

Background:

• Current methods for developing fully human monoclonal antibodies (mAbs) involve transgenic mice or antibody libraries, aiming to minimize immunogenicity.
• Mouse-derived antibodies can elicit an immune response in patients, limiting their therapeutic efficacy and duration.

Purpose of the Study:

• To present a novel computational strategy for generating fully human mAbs from nonhuman variable regions.
• To engineer human antibody characteristics into existing murine mAbs by leveraging human germline repertoire information.

Main Methods:

• Utilized semi-automated computational methods to explore substitutions in complementarity-determining regions (CDRs) and the V(H)/V(L) interface.
• Applied iterative substitutions to the closest human germline sequences for three murine mAbs targeting CD25, VEGF, and TNF-alpha.
• Engineered 59, 46, and 45 substitutions into the variable regions of the parent murine sequences.

Main Results:

• Generated fully human antibody variants with antigen affinities comparable to chimeric mAbs.
• Demonstrated that in vitro functional characterization confirmed retained potency and comparable activity to marketed drugs (daclizumab, bevacizumab, infliximab).
• Engineered mAbs showed sequence identity indistinguishable from naturally occurring fully human antibodies.

Conclusions:

• Established a rational engineering methodology for creating fully human antibody therapeutics from murine mAbs.
• This method offers a simplified approach to generating human monoclonal antibodies, reducing immunogenicity and improving therapeutic potential.
• The engineered antibodies maintain functional potency and therapeutic efficacy comparable to existing treatments.