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

The United States of America as Represented by the Secretary of

Duke University

The United States of America

Other

US Government as Represented by the Secretary of the Army

Hoffmann-La Roche Inc.

University of Illinois

Cetus Corporation

Protein Design Labs, Inc.

University of Delhi

Sanford Research

F. Hoffmann-La Roche Ag

The United States of America, Represented by the Secretary, U.S. Department of Commerce

Ira H Pastan

David J FitzGerald

Masanori Onda

Byungkook Lee

Darell D Bigner

Ulrich Brinkmann

Mark C Willingham

Mitchell Ho

Chien-Tsun Kuan

Richard Beers

Dimiter Stanchev Dimitrov

Vijay K Chaudhary

Robert Kreitman

David J Fitzgerald

Tapan K Bera

Wenhai Liu

Satoshi Nagata

Partha S Chowdhury

Raj K Puri

Michael M Gottesman

Sun-Hee Jung

Kai Chang

David Fitzgerald

Jay A Berzofsky

Rimas J Orentas

Crystal L Mackall

Xiaodong Xiao

Waldemar Debinski

Ronit Mazor

Jeffrey Schlom

Bernard Moss

John Howard Sampson

Kwong-Yok Tsang

Wei Gao

Tamio Mizukami

Cary L Queen

Curt Douglas Wolfgang

George Vasmatzis

Thomas Alexander Waldmann

Edward A Berger

Thomas R Fuerst

Kazumitsu Ueda

James Vincent

Vijay Kumar Chaudhary

Bryan Daehahn Choi

Aaron Vassall

Jaime Eberle

Itai Benhar

Nicholas Obiri

Giuliana Salvatore

Eduardo Agustin Padlan

Yi-Hsiang Huang

Yifan Zhang

Masaki Terabe

Sankar L Adhya

Yen T Phung

Yoram Reiter

Hailan Piao

Mingqing Cai

Patrick C Gedeon

Robert J Kreitman

Raffit Hassan

Tomoko Ise

Elizabeth Mansfield

Junxia Wei

Lee Pai

John Weldon

SangKon Oh

Steven A Rosenberg

Guy Georges

Igor B Roninson

David B Ring

Sabine Imhof-Jung

Yasuhiro Abe

Walter J Laird

Smita K Nair

Matthias Gromeier

Yoshito Numata

Yang Feng

Gerhard Niederfellner

Arthur E Frankel

Bryan Choi

Nan Li

Steven A Feldman

Michael J Bjorn

Vidyalakshmi Chandramohan

Mingqian Feng

Amita Gupta

Charles Pegram

Magnus Essand

Yasuo Tsutsumi

Kenneth Santora

Abhishek Sinha

Xuhui Bao

Janendra Batra

Jeffrey L Windelhake

Masato Ogata

Prior Trevor

Disclosed is a molecule comprising: (a) a first domain, which comprises a targeting moiety; (b) a second domain, which comprises an albumin binding domain (ABD), (c) a third domain, which comprises a furin cleavage sequence ('FCS'), which FCS is cleavable by furin; and (d) a fourth domain, which comprises an optionally substituted Domain III fromexotoxin A (“PE”). Related nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, methods of producing the molecule, methods of treating or preventing cancer in a mammal, and methods of inhibiting the growth of a target cell are also disclosed.

Immunotoxins with albumin binding domain

Camel single-domain monoclonal antibodies that specifically bind human and mouse mesothelin are described. Chimeric antigen receptor (CAR) T cells and antibody conjugates based on the mesothelin-specific antibodies are also described. The disclosed CAR T cells, mesothelin-specific antibodies and conjugates thereof can be used, for example, in the diagnosis or treatment of mesothelin-positive cancers.

Cross species single domain antibodies targeting mesothelin for treating solid tumors

The invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain comprising SEQ ID NOs: 1-6, a transmembrane domain, and an intracellular T cell signaling domain. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.

M971 chimeric antigen receptors

Disclosed is a molecule comprising: (a) a first domain, which comprises a targeting moiety; (b) a second domain, which comprises an albumin binding domain (ABD), (c) a third domain, which comprises a furin cleavage sequence ('FCS'), which FCS is cleavable by furin; and (d) a fourth domain, which comprises an optionally substituted Domain III fromexotoxin A ('PE'). Related nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, methods of producing the molecule, methods of treating or preventing cancer in a mammal, and methods of inhibiting the growth of a target cell are also disclosed.

Polypeptides and proteins that specifically bind to and immunologically recognize human mesothelin582-598 (IP-NGYLVLDLSMQEALS) (SEQ ID NO: 1) are disclosed. Anti-mesothelin binding moieties, nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and conjugates relating to the polypeptides and proteins are disclosed. Methods of reducing mesothelin shed from cell membranes, methods of reducing the activity of TNF&#x3b1; converting enzyme, methods of detecting the presence of cancer, and methods of treating or preventing cancer are also disclosed.

Anti-mesothelin polypeptides and proteins

Regional, tumor-targeted, cytotoxic therapy, such as D2C7-immunotoxin (D2C7-IT), not only specifically target and destroy tumor cells, but in the process initiate immune events that promote an in situ vaccine effect. The antitumor effects are amplified by immune checkpoint blockade which engenders a long-term systemic immune response that effectively eliminates all tumor cells.

Combination therapy of immunotoxin and checkpoint inhibitor

Polypeptides and proteins that specifically bind to and immunologically recognize B-Cell Maturation Antigen (BCMA) are disclosed. Chimeric antigen receptors (CARs), anti-BCMA binding moieties, nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and conjugates relating to the polypeptides and proteins are also disclosed. Methods of detecting the presence of cancer and methods of treating or preventing cancer are also disclosed.

Anti-BCMA polypeptides and proteins

Mesothelin is a differentiation antigen present on the surface of ovarian cancers, mesotheliomas and several other types of human cancers. Because among normal tissues, mesothelin is only present on mesothelial cells, it represents a good target for antibody mediated delivery of cytotoxic agents. The present invention is directed to improved recombinant immunotoxins comprising anti-mesothelin antibodies, including Fv molecules with particularly high affinity for mesothelin, and aExotoxin moiety which has been modified to reduce its immunogenicity and protease sensitivity and providing a better cytotoxicity for cells which express mesothelin. The RITs are well-suited for the treatment of cancers of the ovary, stomach, squamous cells, mesotheliomas and other malignant cells expressing mesothelin.

Recombinant immunotoxin targeting mesothelin

Disclosed herein are isolated human monoclonal antibodies that specifically bind human CD22 with a dissociation constant (K) of 25 nM or less. Nucleic acids encoding these antibodies, expression vectors including these nucleic acid molecules, and isolated host cells that express the nucleic acid molecules are also disclosed. The antibodies can be used to detect human CD22 in a sample. In some cases, CD22 is soluble CD22. Methods of diagnosing a B-cell malignancy, or confirming a B-cell malignancy diagnosis, are disclosed herein that utilize these antibodies. Methods of treating a subject with a B-cell malignancy are also disclosed.

Human monoclonal antibodies specific for CD22

The invention provides aexotoxin A (PE) comprising an amino acid sequence having a substitution of one or more B-cell and/or T-cell epitopes. The invention further provides related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions. Methods of treating or preventing cancer in a mammal, methods of inhibiting the growth of a target cell, methods of producing the PE, and methods of producing the chimeric molecule are further provided by the invention.

exotoxin A with less immunogenic T cell and/or B cell epitopes

The invention provides aexotoxin A (PE) comprising an amino acid sequence having a substitution of one or more of amino acid residues E420, D463, Y481, L516, R563, D581, D589, and K606, wherein the amino acid residues are defined by reference to SEQ ID NO: 1. The invention further provides related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions. Methods of treating or preventing cancer in a mammal, methods of inhibiting the growth of a target cell, methods of producing the PE, and methods of producing the chimeric molecule are further provided by the invention.

Pseudomonas exotoxin A with less immunogenic B cell epitopes

We tested the in vitro and in vivo efficacy of a recombinant bispecific immunotoxin that recognizes both EGFRwt and tumor-specific EGFRvIII receptors. A single chain antibody was cloned from a hybridoma and fused to toxin, carrying a C-terminal peptide which increases retention within cells. The binding affinity and specificity of the recombinant bispecific immunotoxin for the EGFRwt and the EGFRvIII proteins was measured. In vitro cytotoxicity was measured. In vivo activity of the recombinant bispecific immunotoxin was evaluated in subcutaneous models and compared to that of an established monospecific immunotoxin. In our preclinical studies, the bispecific recombinant immunotoxin, exhibited significant potential for treating brain tumors.

Dual specific immunotoxin for brain tumor therapy

We have constructed a polynucleotide encoding a bispecific antibody engaging molecule which has one arm that specifically engages a tumor cell which expresses the human EGFRvIII mutant protein on its surface, and a second arm that specifically engages T cell activation ligand CD3. The polynucleotide is codon optimized for expression in CHO cells. The subunits of the engaging molecules are organized to achieve greater efficiency. These are therapeutic agents.

Human bispecific EGFRvIII and CD3 antibody engaging molecules

Growing community of inventors

Potomac, MD, United States of America

Ira H Pastan