Passive immunotherapy using plant-derived broadly HIV-1 neutralizing MAbs to prev
Department of Health and Human Services
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AbstractDESCRIPTION (provided by applicant): In the absence of specific intervention and with extended breast-feeding mother-to- child-transmission of HIV reaches a rate of ~35 % and infection of ~700,000 babies worldwide. Passive immunotherapy with a small numberof broadly neutralizing monoclonal antibodies (MAbs) in SHIV challenged macaques bodes well for the ability of infusion of neutralizing MAb to prevent such transmission in humans. However the amount of MAb required would overwhelm current fermenter-basedproduction systems and an alternate system for MAb production is a high priority. Due to recent innovations, transient plant (Nicotiana bentamiama) expression platforms now represent some of the most rapid, cost effective and productive in existence; capable of producing grams of recombinant MAbs in weeks. In the Phase I feasibility study, high mannose and complex glycoforms of 2G12, 2F5, 4E10 b12, m43 and m9 MAbs were transiently produced at 80-100 mg/kg leaves (except for the scFv m9) and each exhibited similar, and, in the case of b12, better neutralizing titers than their CHO-derived counterparts although differences were observed in antibody dependent cellular cytoxicity activity. In Phase II, high mannose, complex and 11,3-fucose/21,2-xylose-negative/low glycoforms of three new broad and potent MAbs (PG9, PG16, VRC01), in addition to b12 and 2G12 from Phase I, will be produced in a p19 enhanced plant expression system (200- 500mg/kg) and assessed for in vitro for both their neutralizing and F3-mediatedantibody effector activity (ADCC and ADCVI). Six hundred mg of those forms with the best neutralizing activity will be produced for pharmacokinetics, immunogenicity and protection studies in macaques. Single MAbs and a cocktail of MAbs will be injected i.v. or s.c. weekly and vaginally challenged with a low dose of SHIV bi-weekly to more closely mimic doses encountered in human heterosexual exposure. These results will provide the preclinical data for transition into human trials. PUBLIC HEALTH RELEVANCE: With an ever increasing number of mother-to-baby-transmissions of the HIV virus in the developing world, the production of and immunotherapy with monoclonal antibodies that strongly neutralizing activity a high priority. However the facilities to manufacture such large amounts has not been available. In Phase I we showed that MAbs can be rapidly produced in a new transient plant expression systems in high levels and have similar (or better) neutralizing activity as the conventional CHO-derived forms.In Phase II we shall used an enhanced transient expression system to produce large amounts of new potent MAbs and assess their ability to protect macaques against SHIV virus infection.
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