A Novel Antibody Engineering Platform to Improve Antibody Stability
To defend against infection, humans and other animals produce antibodies. Antibodies can also be used to diagnose and treat some diseases and to detect toxins and pathogens. While global demand for antibody therapeutics is growing dramatically, antibodies are relatively fragile, and tend to be unstable outside controlled laboratory conditions. Scientists at Argonne National Laboratory have developed a cost-effective engineering strategy for improving antibody stability.Description
Argonne scientists have developed a sequence-guided, semi-rational strategy for improving thermal stability of antibodies and antibody fragments. The method is based on screening a limited number of amino acid variations that have been observed in functional antibody variable domains. By restricting amino acid screening to changes that have been documented in functional antibodies, dramatic stabilization can be achieved using minimal experimental effort compared to randomized or combinatorial approaches.
In the development of robust antibodies for biosensors, the method has been used to stabilize antibody fragments (scFvs) to unprecedented levels (Figures 1 and 2). A generation of scFvs that maintain function after incubation for more than 2 hours at 70°C has been accomplished.
In the development of therapeutic antibodies, the method has been applied to full-length therapeutic antibodies with great success. A panel of variants of a blockbuster anti-cancer antibody has been generated that has a 10-11° C higher melting temperature (Tm) compared to the wild type antibody (Figure 3). Potential benefits of stabilized antibodies include increased serum half-life, reduced immunogenicity, longer shelf life, simplified formulation, and decreased cold train and production costs. Furthermore, the method’s emphasis on sequence variations seen in functional antibodies reduces the chance that stabilization will introduce immunogenic epitopes.Benefits
- Method is systematic, fast, inexpensive and highly reliable;
- Engineered antibody is usable in less than optimal environments; and
- Antibody stability level can be fine-tuned to create multiple products from a single antibody.
- Optimization of therapeutic antibodies;
- Diagnostic and detection kits for pathogens;
- Biosensors; and
- Imaging and radiotherapy.
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METHODS FOR SYSTEMATIC CONTROL OF PROTEIN STABILITY
Methods and compositions to control the stability of proteins with special emphasis on antibodies and proteins with antibody-like structures, e.g., having an "immunoglobulin-like" fold, are described. Controlling the stability facilities different applications for a protein with the same function, but different stability.
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