Rapid optimization and prototyping for therapeutic antibody-like molecules

Area of Science:

• Biotechnology
• Immunotherapy
• Molecular Engineering

Background:

• Multispecific antibody-like molecules offer therapeutic potential but face design challenges.
• Current therapeutic molecule design is complex, requiring concurrent engineering of affinity, avidity, effector functions, and pharmaceutical properties.
• Only one trivalent antibody, catumaxomab, has shown clinical utility, highlighting design difficulties.

Purpose of the Study:

• To present a rapid prototyping approach for optimizing multispecific antibody design.
• To demonstrate the approach through a case study of MM-141, a bispecific antibody targeting IGF-1R and ErbB3.
• To improve the bioactivity and stability of a previously developed MM-141 proof-of-concept molecule.

Main Methods:

• Utilized modular design and yeast display of antibody libraries.
• Employed high-throughput biophysical profiling and library-scale thermal challenge assays.
• Applied structured-guided antibody design to discover optimized single-chain variable fragments (scFvs).

Main Results:

• Discovered stable and active anti-IGF-1R and anti-ErbB3 scFvs.
• Reformatted optimized modules into diverse tetravalent bispecific antibodies.
• Achieved complete blockade of growth factor signaling, serum stability, and suitable properties for clinical development.

Conclusions:

• The rapid prototyping approach successfully optimized multispecific antibody parameters within one campaign cycle.
• The re-engineered MM-141 molecules demonstrated significant improvements in bioactivity and stability.
• This approach is applicable to optimizing other classes of bispecific and multispecific antibody-like molecules.