Bispecifics and Engineered Antibodies

Sutro’s cell-free expression technology provides a rapid and powerful platform for the discovery and development of antibodies that bind simultaneously to two separate antigens (bispecific antibodies). Bispecific antibodies can be designed to achieve different purposes:

  • To bring an antigen-expressing cell in close proximity to a killing cell, e.g. bispecifics that comprise a tumor cell antigen-binding site and a T-cell or NK cell antigen-binding domain
  • To increase the apparent affinity of binding to an antigen, using avidity, e.g. by binding two separate proteins or two epitopes of a single protein on a cell’s surface
  • To increase the relative selectivity of binding of an antibody to a particular antigen on disease tissue over normal tissue by using a similar avidity approach, e.g. two antigens expressed on the same diseased cell
  • To increase the internalization rates of particular antigens on a cell’s surface by cross-linking two cell surface proteins or by binding to two different epitopes on a given antigen. This emerging approach could also be used to more efficiently deliver warhead payloads to tumor cells using a bispecific antibody-drug conjugate

While many different bispecific antibody formats have been exemplified using cell-based expression systems, and some have been successful enough to show promise as new classes of therapeutics, the precise geometry and spatial orientation of binding domains, linkers and functional domains can be a challenge to optimize. Additionally, the use of cell-based systems has revealed immense difficulties in their expression efficiency, particular at larger scale, often resulting in poorly folded and aggregated material. Consequently, using traditional cell-based technologies prevents researchers from discovering and developing bispecific candidates with optimal therapeutic indices and can result in products with unpredictable pharmacokinetic properties, stability and efficacy.

Sutro’s technology has the ability to perform rapid expression and characterization of many variants early in discovery to define structure-activity relationships and thereby optimize:

  • Binding efficiency to each target
  • Spatial orientation and linker design
  • Target killing efficiency
  • Protein expression and folding efficiency
  • Stability

Sutro can optimize rapidly for all of these variables with exquisite specificity, resulting in optimized product candidates.