New York University

Other

Yeda Research and Develpment & Co. Ltd

Daniel Meruelo

Gad Lavie

Yehuda Mazur

Christine L Pampeno

Alicia Hurtado

David Lavie

Takayuki Yoshimoto

Christine Pampeno

Alicia Hurtado Martinez

Jen-Chieh Tseng

Koichi Ono

Kouichi Ohno

Michel Revel

Dalia Rotman

Vincent Vande Velde

Iris Scherwitzl

Tomer Granot

Yoshihide Yamanashi

Kelly Victoria Jamieson

Brandi A Levin

Stevan Ralph Hubbard

Kuoichi Ono

Provided are polynucleotides and viral vectors, e.g., alphavirus or Sindbis viral vectors, encoding multiple, e.g., two or more, epitopes of at least one tumor associated antigen, in which each epitope is separated by a processing or enzyme cleavage site. The encoded epitopes may be the same or different. Also provided are polynucleotides and viral vectors, particularly, alphavirus or Sindbis viral vectors, encoding an immune checkpoint protein, or a ligand binding portion thereof. The immune checkpoint protein or ligand binding portion thereof may be fused to immunoglobulin domains, e.g., an Ig hinge domain and an Ig heavy chain constant domain. Methods of treating subjects having a cancer or tumor, e.g., a TAA-expressing tumor, with the described viral vectors are provided. Treatment of subjects with the vectors, the checkpoint inhibitor molecules and/or other immunomodulatory components, generate an anti-cancer or anti-tumor immune response resulting in increased survivability of tumored subjects and epitope spreading.

Induction and enhancement of antitumor immunity involving virus vectors expressing multiple epitopes of tumor associated antigens and immune checkpoint inhibitors or proteins

Provided are polynucleotides and viral vectors, particularly,vectors such as Sindbis viral vectors, which encode an immune checkpoint protein, or a ligand binding portion of the checkpoint protein, or an immune checkpoint protein or ligand binding portion thereof fused to one or more immunoglobulin (Ig) domains, e.g., an Ig hinge region and an Ig heavy chain constant domain. Methods of treating a mammalian subject having a cancer or tumor are provided, in which the viral vectors, e.g., a Sindbis virus vector, encoding the immune checkpoint protein, a ligand binding portion thereof, or a checkpoint protein fusion protein as described, are administered to the subject, resulting in an anti-cancer or anti-tumor immune response, significant reduction in tumor growth in the treated subject and increased survivability.

Induction and enhancement of antitumor immunity involving Sindbis virus vectors expressing immune checkpoint proteins

The subject application is directed to a method for treating a mammal harboring a tumor comprising identifying a tumor associated antigen (TAA) expressed by the tumor and parenterally administering to the mammal a therapeutically effective amount of a Sindbis viral vector carrying a gene encoding the TAA to the mammal sufficient to elicit an immune response directed against the tumor, and thereby treating the tumor.

Method for inducing antitumor immunity using Sindbis viral vectors and tumor associated antigens

Disclosed herein are new defective Sindbis viral vectors made from wild type Ar-339 Sindbis virus, with differences in replicase and envelope proteins between JT vectors and consensus Sindbis virus sequences, and also between JT and Ar-339 vectors. Also disclosed are plasmids used for the production of the vectors, methods for producing the vectors, methods for treating mammals suffering from tumors and pharmaceutical formulations for use in the treatment methods.

Defective Sindbis viral vector comprising an anti-tumor gene

Disclosed herein are methods for treating a mammal harboring a solid tumor which expresses higher levels of High Affinity Laminin Receptors (LAMR) than normal cells of the same lineage comprising systematically administering to a mammal in need of such treatment a therapeutically effective amount of a Replication Competent (RC) Sindbis virus vector, wherein said vector encodes a suicide gene.

Tumor therapy with replication competent sindbis viral vectors

A human laminin receptor crystal is disclosed. Methods are disclosed for using various computer and non-computer means in order to develop models for use in the development of novel therapeutics that block and/or mimic laminin receptor interactions in the setting of, among others, Alzheimer's disease, other neurological disorders, cancer, and viral and bacterial infections.

Human laminin receptor crystal and uses thereof

Disclosed herein are new defective Sindbis viral vectors made from a novel Helper plasmid, with differences in envelope proteins between JT vectors and consensus Sindbis virus sequences, and also between JT and Ar-339 vectors. Also disclosed are vectors produced using the plasmid, methods for producing the vectors, methods for treating mammals suffering from tumors and pharmaceutical formulations for use in the treatment methods.

Defective sindbis viral vectors

Disclosed herein are methods for identifying cancer cells and monitoring anti-cancer therapy in the body of a mammal by systemically delivering Sindbis viral vectors. The vector can specifically target and identify tumor cells in mice growing subcutaneously, intraperitoneally, intrapancreatically, or in the lungs. These findings demonstrate the remarkable specificity of the Sindbis vector system that is relatively safe and can specifically target tumor cells throughout the body via the bloodstream.

Method for detecting cancer cells and monitoring cancer therapy

The present invention relates to methods and compositions for treating tumors using vectors that preferentially target tumor cells. In particular, the invention relates to alphavirus-based, preferably Sindbis virus-based, vectors and to non-alphavirus-based vectors, which have a preferential affinity for high affinity laminin receptors (HALR). These vectors are efficiently targeted to tumors and have the ability to cause tumor necrosis.

Tumor therapy with high affinity laminin receptor-targeted vectors

The present invention pertains to packaging cell lines useful for the production of viral vectors, particularly packaging cell lines for continuous production of Sindbis viral vectors at high efficiency. The packaging cell line comprises an insect cell having DNA that encodes alphavirus structural proteins, replicase and a replicon.

Packaging cell lines for the continuous production of alphavirus vectors

The present invention relates to methods and compositions for treating tumors using vectors that preferentially target tumor cells. In particular, the invention relates to Sindbis virus vectors which have a preferential affinity for high affinity laminin receptors (HALR). These vectors are efficiently targeted to tumors and have the ability to cause tumor necrosis.

Tumor therapy with alphavirus-based and high affinity laminin receptor-targeted vectors

Target cell specificity of delivery vectors is provided by incorporation of a target cell specific binding domain by the use of any binding domain, which binds specifically to a binding site on the target cell. The binding site may be endogenous to the target cell, provided by engineering the target cell, or a suitable binding site may be associated with the target cell. Target cell may also be associated with a CVR polypeptide to provide specificity for the delivery vector. The association of the CVR polypeptide confers target cell specificity for a second virus host cell range, which specificity differs from the viral host cell range of the endogeneous target cell or animal host cell viral receptors. The CVR polypeptide may thus comprise a chimeric virus binding site which binds a second virus env binding domain specific for a second virus host cell range, selected from at least one of the group consisting of amphotropic, polytropic, xenotropic, ecotropic and tissue specific.

Chimeric viral receptor polypeptides, human viral receptor polypeptides and uses thereof

Novel antiviral (including antiretroviral) compounds are mono- or dicarboxylic acid esters of hypericin in which one or both of the methyl groups of hypericin are substituted by carboxylic acid ester groups of the formula COOR in which R is alkyl, the chain of which is optionally interrupted by one or more oxygen or sulphur atoms. R is preferably methyl, ethyl, propyl, butyl, 2-methoxyethyl or 2-(2-methoxyethoxy)ethyl. The compounds may be formulated into pharmaceutical compositions and may be used in any manner which has previously been known for hypericin.

Antiviral agents

The invention concerns an improvement in the art of inserting and expressing foreign gene into eukaryotic cells. The invention particularly concerns methods and compositions whereby viral vectors can be used to insert and express foreign genes into specifically cells having particular differentiation antigens. A method of determining which differentiation antigens can be used is taught. The invention encompasses complexes of viral particles and adapters that cause the binding and internalization of the vector particles such that a gene of interest in the particle is expressed.

Growing community of inventors

Scarborough, NY, United States of America

Daniel Meruelo