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Anti-Drug Antibodies in Pigtailed Macaques Receiving HIV Broadly Neutralising Antibody PGT121.

ABSTRACT: Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.

SUBMITTER: Lee WS

PROVIDER: S-EPMC8636046 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHIV-1 infections occur following viral exposure at anogenital mucosal surfaces in the presence of semen. Semen contains immunosuppressive and pro-inflammatory factors. Semen from HIV-1-infected donors contains anti-HIV-1 antibodies. We assessed if passively infused anti-HIV-1 neutralizing antibody conferred protection from rectal SHIVSF162P3 challenge at semen exposed mucosae.MethodsWe pooled seminal plasma from HIV-1-infected donors. The pool was screened by ELISA for antibodies against HIV-1SF162 gp140. The ability of seminal plasma to inhibit macaque NK cells from responding to direct and antibody-dependent stimulation was assessed. The ability of seminal plasma to inhibit macaque granulocytes from mediating oxidative burst was also assessed. To demonstrate viral infectivity in the presence of seminal plasma, macaques (n = 4) were rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. To evaluate if anti-HIV-1 neutralizing antibody confers protection against rectal SHIV challenge at semen exposed mucosae, eight macaques were intravenously infused with PGT121, either wild type (n = 4) or the Fc receptor binding deficient LALA variant (n = 4), and rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma.FindingsAnti-HIV-1SF162 gp140 antibodies were detected in seminal plasma. Seminal plasma inhibited direct and antibody-dependent NK cell activation and granulocyte oxidative burst in vitro. Rectal SHIVSF162P3 challenge of control macaques following seminal plasma exposure resulted in infection of all animals. All macaques infused with wild type or LALA PGT121 and challenged with SHIVSF162P3 following seminal plasma exposure were protected.InterpretationPGT121 conferred protection against rectal SHIVSF162P3 challenge at semen exposed mucosae. Future research should investigate if semen alters protection conferred by antibodies more dependent on non-neutralizing functions.FundingThis work was supported by a grant from the Australian National Health and Medical Research Council (APP1124680).

Project description: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 naïve 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 naïve 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.

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Anti-Drug Antibodies in Pigtailed Macaques Receiving HIV Broadly Neutralising Antibody PGT121.

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