Passive immunotherapy using plant-derived broadly HIV-1 neutralizing MAbs to prev
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AbstractDESCRIPTION (provided by applicant): While many HIV vaccine regimens have elicited robust viral-specific T cell responses, they have been unable to prevent infection. To date, passive immunotherapy with a small number of broadly neutralizing monoclonal ant ibodies (MAbs) given in combination have afforded the best protection against SHIV challenge in monkeys. However, in a global context, the large multiple doses required will create excessive demands on existing expensive microbial fermentation or cell-base d production systems. Plant expression will provide an inexpensive, safe, and rapidly scalable alternative. Genetically engineered plants have been successfully used to produce many complex proteins, as diverse as IgG, sIgA, vaccine antigens, enzymes and g rowth factors. The aim of this Phase I study is to produce highly expressing MAbs in plants using Agrobacterium infiltration/ injection and assess their ability to broadly neutralize HIV-1 isolates in vitro. Several well characterized envelope-specific MAb s will be produced in tobacco; 2G12, 2F5, 4E10, IgG1b12 as well as a MAb against a CD4-inducible gp120 epitope. In order to examine, the effect of N-glycosylation on neutralization by these MAbs, both the ER- retained high mannose and the secreted compl ex glycan forms will be produced and compared to CHO-derived proteins. Concomitant with these studies, the slower process of generating stable transgenic tobacco plants will be initiated. This will be aided by coexpression of the DsRed fluorescent marker to identify antibody expressing lines and trace transgenic offspring. In the current environment, the use of a non-food, non-feed crop to produce important therapeutic proteins offers many advantages. In Phase II, those MAbs that are both expressed at high levels and have strong neutralizing activity will be produced by either transgenic plants or by large scale transient expression of tobacco plants and tested for their ability to prevent infection of monkeys challenged with an SHIV isolate. PUBLIC HEALTH RELEVANCE: Unlike HIV vaccines, the passive transfer of large amounts of monoclonal antibodies that broadly neutralize HIV virus has shown dramatic protection against a lethal challenge with a SHIV isolate given one day later. However, the cost of producin g these recombinant proteins in traditonal expression systems would be exorbitant and a more inexpensive system is a high priority. In this proposal, these MAbs will be produced in tobacco plants and their ability to neutralize HIV in vitro and to protect monkeys in vivo will be compared to currently used and expensive CHO-derived MAbs.
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