The United States of America, As Represented by the Secretary, Department of Health and Human Services

The United States of America As Represented by the Department of Health

Institut National De La Sante Et De La Recherche Medicale

The United States of America

Edward A Berger

Steven A Rosenberg

Ira H Pastan

Richard A Morgan

Bernard Moss

Li Liu

Tamio Mizukami

Thomas R Fuerst

Christopher C Broder

Vijay K Chaudhary

Yu Feng

David Fitzgerald

Paul E Kennedy

Christie M Del Castillo

David J FitzGerald

Philip M Murphy

Vijay Kumar Chaudhary

Barna Dey

Christophe Combadiere

Miriam Triyatni

Bhavik Patel

Mustafa H Ghanem

Ghalib Alkhatib

Bertrand Saunier

The present disclosure is directed to novel multispecific chimeric antigen receptor (CAR) proteins and DNA sequences encoding these proteins. The CARs comprise at least two extracellular domains fused, via a transmembrane domain to a cytoplasmic signaling domain comprising two signaling domains. The disclosure further relates to nucleic acids encoding the novel CARs, to host cells expressing the novel CARs, and to methods of using the CARs to co-stimulate effector functions in the cells and for using cells expressing the receptors for treatment of disease and viral infections. The disclosure also relates to methods of generating a recombinant T cell with reduced susceptibility to HIV infection.

Chimeric antigen receptors to control HIV infection

Provided herein is a mammalian cell transformed to contain a plasmid encoding a T7 or SP6 promoter operably linked to one or more HCV genes, a subgenomic replicon from a flavivirus and a cytoplasmic T7 and SP6 RNA amplification system. Also provided herein are isolated replication-competent HCV particles produced by the method comprising the steps of providing a transformed mammalian cell according to the first embodiment, culturing the cell, and recovering the replication-competent HCV particles from the cell culture. Provided herein are isolated HCV structural proteins produced by the method comprising the steps of providing a transformed mammalian cell according to the first embodiment, culturing the cell, and recovering the HCV structural proteins from the cell culture. Further provided herein is a system for assaying HCV entry into a cell comprising a first plasmid encoding a T7 or SP6 promoter operably linked to an HCV polynucleotide comprising at least the 5'-UTR to NS2 operably linked to an EMCV IRES in frame with an SP6 or T7 polymerase gene, respectively, a first host cell line expressing a replicon from a flavivirus and comprising a cytoplasmic T7 and SP6 RNA amplification system, a second plasmid encoding a reporter gene operably linked to both T7 and SP6 promoters in tandem, and a second host cell line comprising a cytoplasmic T7 polymerase or SP6 polymerase RNA amplification system.

Flavivirus-based system for production of hepatitis C virus (HCV)

This invention relates to bispecific fusion proteins effective in viral neutralization. More specifically, such proteins have two different binding domains, an inducing-binding domain and an induced-binding domain, functionally linked by a peptide linker. Such proteins, nucleic acid molecules encoding them, and their production and use in preventing or treating viral infections are provided. One prototypical bispecific fusion protein is sCD4-SCFv(17b), in which a soluble CD4 fragment (containing domains D1 and D2) is fused to a single chain Fv portion of antibody 17b via a linker.

Chimeric protein for prevention and treatment of HIV infection

The susceptibility of human macrophages to human immunodeficiency virus (HIV) infection depends on cell surface expression of the human CD4 molecule and CC cytokine receptor 5. CCR5 is a member of the 7-transmembrane segment superfamily of G-protein-coupled cell surface molecules. CCR5 plays an essential role in the membrane fusion step of infection by some HIV isolates. The establishment of stable, nonhuman cell lines and transgenic mammals having cells that coexpress human CD4 and CCR5 provides valuable tools for the continuing research of HIV infection. In addition, antibodies which bind to CCR5, CCR5 variants, and CCR5-binding agents, capable of blocking membrane fusion between HIV and target cells represent potential anti-HIV therapeutics for macrophage-tropic strains of HIV.

CC chemokine receptor 5 DNA, new animal models and therapeutic agents for HIV infection

The susceptibility to human immunodeficiency virus (HIV) infection depends on the cell surface expression of the human CD4 molecule and a human fusion accessory factor associated with HIV infection (CXCR4). CXCR4 is a member of the 7-transmembrane segment superfamily of G-protein-coupled cell surface molecules. CXCR4 plays an essential role in the membrane fusion step of HIV infection. The establishment of stable cell lines that coexpress human CD4 and CXCR4 provides valuable tools for the continuing research of HIV infection and the development of more effective anti-HIV therapeutics.

Cells expressing both human CD4 and a human fusion accessory factor associated with HIV infection

A chimeric gene directing the synthesis of hybrid recombinant fusion protein in a suitable expression vector has been constructed. The fusion protein possesses the property of selective cytotoxicity against specific virus-infected cells. A CD4(178)-PE40 hybrid fusion protein has been made for selectively killing HIV-infected cells.

Cytotoxic agent against specific virus infection

CD-4/cytotoxic gene fusions

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Rockville, MD, United States of America

Edward A Berger