Meditope-enabled Antibodies

Site-specific carving to develop meditope-enabled antibodies is a novel strategy for antibody-drug conjugate (ADC). The technology turns an antibody into a “Lego-like” piece by switching out a few amino acids and the designed piece can be used to combine other matched pieces. It is a novel antibody platform technology facilitating to expand antibody functionality.

Observing the three dimensional structure of antibodies, we can find that there is a naturally occurring pocket of space in the Fab region of an antibody. The inserted molecule nestled in the pocket of space, usually a peptide, is called meditope. Based on the characteristic, the identified meditope-binding site can be grafted to different antibodies, and then the designed meditope-enabled antibody can be engineered to accommodate different compounds conveniently by first conjugating the compound to a meditope. This platform can be used as a new way to generate new ADCs, develop reagents for antibody-pretargeted imaging, etc. For ADC generation, the platform has many advantages. It does not need chemical conjugation to attach toxins. When we want to attach different compounds to a meditope-enabled antibody, it’s not necessary to reengineer the antibody. All the engineering and conjugation work only occurs on the meditope peptide-compounds conjugate instead, which is easier to engineer an antibody. Therefore, the platform, swapping out one conjugate for another, enables generation and evaluation of candidates more efficiently. On the other side, without reengineering antibodies obviates the exposure of a present antibody surface to the host immune system which is unlikely to see or recognize the location of the binding site and the amino acid sequences, so the novel platform should not increase antibody immunogenicity. In ADC development, antibody engineering should not interfere with antibody-antigen binding, which has been validated for meditope occupancy. DAR (drug-to-antibody ratio, the number of cytotoxic molecules attached to an antibody) is another important consideration. The DAR of most of current ADCs that are in clinical trials is 2-4. In order to decrease the heterogeneity of ADC, DAR should be better controlled. The technology platform enables ADCs with homologous and better controlled DAR. Collectively, the unique technique is an alternative strategy to employ a noncovalent linker, meditope, to add functionality to meditope-enabled antibodies. It has the potential to offer opportunities to improve multiple antibody-based technologies including imaging, diagnostics, therapeutic delivery, etc.

There are various strategies used for antibody modification and conjugation:

• Cysteine-based conjugation
• Lysine-based conjugation
• Carbohydrate-based conjugation
• Unnatural amino acids-based conjugation
• Thio-engineered antibody
• Enzymatic modified antibody
• UV photocrosslinking(UV-NBS)
• Meditope-enabled antibodies

References

1. Joshua M. Donaldson, et al. Identification and grafting of a unique peptide-binding site in the Fab framework of monoclonal antibodies. Proc Natl Acad Sci U S A. 2013 Oct 22; 110(43):17456-61.
2. Kendra N. Avery, et al. Development of a high affinity, non-covalent biologic to add functionality to Fabs. Sci Rep. 2015 Jan 15; 5:7817.



For research use only. Not intended for any clinical use.