Paper of the month: Framework Mutations of the 10-1074 bnAb Increase Conformational Stability, Manufacturability, and Stability While Preserving Full Neutralization Activity
Summary
The human immunodeficiency virus (HIV) still presents a significant challenge to patients and healthcare systems as there is no cure or effective vaccine for this virus. The lack of effective vaccines has led to preventative strategies being the primary method for dealing with HIV. While there are estimated to be around 37 million cases of HIV globally, 70% of these cases occur within the Sub-Saharan African region. This presents a challenge in developing new biologics as the quality of the “cold-chain” may vary during transport and storage, necessitating highly stable antibody biologics.
Within this article, mutations of the broadly neutralizing antibody (bnAb) 10-1074 are investigated as candidates for a prophylactic treatment for HIV. Incorporating isothermal chemical denaturation into the suite of analytical techniques used, the sequence of the 10-1074 bnAb was optimized for increased conformational stability. These improvements aim to improve manufacturability and storage parameters.
Investigations used two rounds to arrive at the final few optimized bnAb. The first round measured constructs resulting from single-site mutations, while the second round combined beneficial single-site mutations to improve the conformational stability of the bnAb further. Isothermal chemical denaturation was used within the second round to distinguish better the difference between candidates, and when combined with thermal denaturation measurements revealed the HV:T108R residue as critical to improving the conformational stability of the bnAb.
Citation
Kerwin, B. A. et al. Framework Mutations of the 10-1074 bnAb Increase Conformational Stability, Manufacturability, and Stability While Preserving Full Neutralization Activity. Journal of Pharmaceutical Sciences 109, 233–246 (2020).
DOI
