• Introduction of the YTE mutation into the non-immunogenic HIV bnAb PGT121 induces anti-drug antibodies in macaques

      Rosenberg, Y.J.; Lewis, G.K.; Montefiori, D.C. (Public Library of Science, 2019)
      Recombinant antibodies play increasingly important roles as immunotherapeutic treatments for human cancers as well as inflammatory and infectious diseases and have revolutionized their management. In addition, their therapeutic potential may be enhanced by the introduction of defined mutations in the crystallizable fragment (Fc) domains eg YTE (M252Y/ S254T/T256E) and LS (M428L/N434S), as a consequence of increased half-lives and prolonged duration of protection. However, the functional properties of any biologic may be compromised by unanticipated immunogenicity in humans, rendering them ineffective. Several potent broadly neutralizing HIV monoclonal antibodies (bnAbs) have been identified that protect against SHIV challenge in macaque models and reduce HIV viremia in HIV-infected individuals. In the present study, the pharmacokinetics and immunogenicity of one or more 5mg/kg subcutaneous (SC) injections in naive macaques of the HIV bnAb PGT121 and its PGT121-YTE mutant, both produced in plants, have been compared towards prolonging efficacy. Induction of anti-drug/anti-idiotypic antibodies (ADA, anti-id) has been monitored using both binding ELISAs and more functional inhibition of virus neutralization (ID50) assays. Timing of the anti-Id responses and their impact on pharmacokinetic profiles (clearance) and efficacy (protection) have also been assessed. The results indicate that ADA induction in naive macaques may result both from injection of the previously non-immunogenic PGT121 into pre-primed animals and also by the introduction of the YTE mutation. Binding ADA antibody levels, induced in 7/10 macaques within two weeks of a first or second PGT121-YTE injection, were closely associated with both reduced pharmacokinetic profiles and loss of protection. However no correlation was observed with inhibitory ADA activity. These studies provide insights into both the structural features of bnAb and the immune status of the host which may contribute to the development of ADA in macaques and describe possible YTE-mediated changes in structure/orientation of HIV bnAbs that trigger such responses.
    • Shaping brain structure: Genetic and phylogenetic axes of macroscale organization of cortical thickness.

      Valk, Sofie L; Xu, Ting; Margulies, Daniel S; Masouleh, Shahrzad Kharabian; Paquola, Casey; Goulas, Alexandros; Kochunov, Peter; Smallwood, Jonathan; Yeo, B T Thomas; Bernhardt, Boris C; et al. (American Association for the Advancement of Science, 2020-09-25)
      The topology of the cerebral cortex has been proposed to provide an important source of constraint for the organization of cognition. In a sample of twins (n = 1113), we determined structural covariance of thickness to be organized along both a posterior-to-anterior and an inferior-to-superior axis. Both organizational axes were present when investigating the genetic correlation of cortical thickness, suggesting a strong genetic component in humans, and had a comparable organization in macaques, demonstrating they are phylogenetically conserved in primates. In both species, the inferior-superior dimension of cortical organization aligned with the predictions of dual-origin theory, and in humans, we found that the posterior-to-anterior axis related to a functional topography describing a continuum of functions from basic processes involved in perception and action to more abstract features of human cognition. Together, our study provides important insights into how functional and evolutionary patterns converge at the level of macroscale cortical structural organization.