Plant derived HIV neutralizing mAbs for passive immunotherapy in newborn macaques

DESCRIPTION provided by applicant The identification of highly potent broadly neutralizing antibodies bnAbs against HIV and success in preventing SHIV infection following their passive administration have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV infection However while broad and potent neutralizing activity is an essential prerequisite in vivo properties such as good circulatory stability and no immunogenicity are equally critical for developing a human treatment In the previous Phase I and Phase II studies glycoforms of both first generation bnAbs and more recent potent highly mutated bnAbs NIH G W E PGT PGT PGT PGT PG PG VRC and b have been produced by Agrobacterium mediated transient transfection of Nicotiana benthamiana and assessed neutralizing activity and following admin istration in macaques The results to date indicate that i N glycans within the VL domain impair plasma stability of plant derived bnAbs and ii while PGT and b exhibit no immunogenicity in macaques after multiple injections surprisingly VRC and NIH G W elicit high titer anti idiotypic antibodies following a second injection which specifically bind the administered bnAb or a close family member and inhibit the bnAb in neutralization assays iii both cocktails VRC b and E as well as single PGT delivered either intravenously or subcutaneously both pre and post challenge administration can protect adult macaques These results form the basis of the current Phase IIB proposalandapos s dual approach to develop an efficacious bnAb cocktail by i performing perinatal protection studies in macaques against SHIV challenge which more closely mimic mother to child transmission MTCT ii to extend their circulatory retention time and iii to identify the T cell epitopes on these highly mutated bnAbs which contribute to their immunogenicity and which could potentially compromising their value for prophylaxis and therapy of HIV In addition the rapid production of broadly neutralizing plant derived HIV mAbs in the current study highlights the unique advantages of the transient plant system in terms of speed and versatility pathogen free nature and low tech requirements particularly in the early developmental stages from andquot cloning to preclinical protection studiesandquot PUBLIC HEALTH RELEVANCE With increasing numbers of mother to baby transmissions MTCT of the HIV virus in the developing world production of and passive immunotherapy with potently neutralizing HIV monoclonal antibodies bnAbs is a high priority However the facilities to manufacture such large amounts are not been available In Phase I and II we showed that MAbs can be rapidly produced in a new transient plant expression systems in high levels and have similar neutralizing activity and similar pharmacokinetics as the conventional CHO derived forms However several of these highly mutated bnAbs were shown to be immunogenic potentially comprising their ability as passive immunotherapeutics In Phase II we shall perform protection studies against SHIV virus with potent plant derived bnAbs in newborn macaques that mimic MTCT and further study immunogenicity of the bnAbs