Passive immunotherapeutics are important in post exposure prophylaxis and treatment of infectious diseases. Reagents for passive immunotherapy include convalescent sera and monoclonal antibodies (mAb). Murine, humanized and fully human mAb (fhmAb) share advantages with respect to defined specificity, and enhanced safety profiles. However, only fhmAb possess native effector functions and eliminate risk of immune responses to nonhuman components that have the potential to reduce efficacy and/or cause autoimmune disease. FhmAb that neutralize Rift Valley fever virus (RVFV), Nipah/Hendra virus (NiV/HeV), and West Nile virus (WNV) were created using a fully human fusion partner cell line (MFP-2) and PEL from patients after natural infection (NiV and WNV) or vaccination (RVFV).
In Aim 1 of this project we will characterize these fhmAb in vivo. PBL from immune donors can difficult to obtain, particularly early in the course of an outbreak;thus, alternative strategies are needed whereby fhmAbs with optimized reactivity can be generated using synthetic reagents and in vitro maturation methods. Toward this end we will test (in Aims 2 and 3) the utility of a genetically engineered Veloclmmune? mouse for producing fhmAb from recombinant antigens representing NiV and Chikungunya virus (CHIKV). Functionality of Veloclmmune-drived mAb to NiV will be compared to that of the mAb generated with MFP-2. Furthermore, (Aim 4) we will apply two complementary methods for in vitro optimization of mAb reactivity: a yeast dual-display system that allows for in vitro mutation of cloned sequences followed by high throughput selection of reactive variants in a yeast system, and somatic hypermutation using the Ramos cell and/or activation induced cytidine deaminase (AID) systems.
Specific Aims are: (1) Characterize biological efficacy of existing fhmAb to RVFV, NiV/HeV and WNV;( 2) Generate fhmAb from protective Veloclmmune mAb to NiV and CHIKV;(3) Characterize Veloclmmune immune response and functionality of generated mAb;(4) Use recombinant genetics, mutagenesis, and somatic hypermutation to optimize mAb reactivity.
Passive immunotherapy has an established track record in post exposure prophylaxis and treatment of infectious diseases and will continue to be a significant primary or complementary line of defense. With this project we will generate safe and specific fully human monoclonal antibody (fhmAb) therapeutics for Category A-C agents and establish a universal platform for efficiently generating these tools from entirely synthetic source materials, enabling a swift response to newly identified disease threats.
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