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

Duke University

Richard Beers

Ira H Pastan

Masanori Onda

Robert Kreitman

Wenhai Liu

Ronit Mazor

Aaron Vassall

Jaime Eberle

Giuliana Salvatore

Satoshi Nagata

Darell D Bigner

Partha S Chowdhury

Yoshito Numata

Robert J Kreitman

John Weldon

Kenneth Santora

Abhishek Sinha

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

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

Pseudomonas exotoxin a with less immunogenic T cell and/or B cell epitopes

[object Object]

The present invention provides improvedExotoxin A (PE) molecules with high cytotoxicity and reduced immunogenicity, compositions containing the improved (PE), and methods of use.

Recombinant immunotoxins are fusion proteins composed of the Fv domains of antibodies fused to bacterial or plant toxins. RFB4 (Fv)-PE38 is an immunotoxin that targets CD22 expressed on B cells and B cell malignancies. The present invention provides antibodies and antibody fragments that have improved ability to bind the CD22 antigen of B cells and B cell malignancies compared to RFB4. Immunotoxins made with the antibodies and antibody fragments of the invention have improved cytotoxicity to CD22-expressing cancer cells. Compositions that incorporate these antibodies into chimeric immunotoxin molecules that can be used in medicaments and methods for inhibiting the growth and proliferation of leukemia and lymphoma cells.

Mutated anti-CD22 antibodies with increased affinity to CD22-expressing leukemia cells

Mutated Anti-CD22 antibodies with increased affinity to CD22-expressing leukemia cells

CD30 is a receptor expressed on cells of Hodgkin's disease and certain leukemias. The extracellular portion of CD30 is cleaved, releasing a form known as sCD30. The invention relates in part to the discovery that a residual, extracellular 'stalk' of CD30 remains after cleavage of sCD30. The stalk provides an advantageous and previously unrecognized target for immunotoxins. The invention provides antibodies that bind to the CD30 stalk or to epitopes destroyed upon the cleavage of CD30 which results in the stalk. The invention further provides new anti-CD30 antibodies that form effective immunotoxins and are particularly suitable for making disulfide stabilized Fv ('dsFv')-immunoconjugates. The dsFv immunoconjugates can be used as reagents to label CD30-expressing cancer cells or to inhibit the growth of CD30-expressing cancer cells. Moreover, the invention provides anti-CD30 antibodies that activate complement-dependent cytotoxicity.

Anti-CD30 stalk and anti-CD30 antibodies suitable for use in immunotoxins

The invention provides antibodies to a mutant form of the epidermal growth factor receptor known as EGFRvIII found only or primarily on the surface of glioblastoma cells, and on cells of breast, ovarian and non-small cell lung carcinomas. The antibodies provided by the invention have the complementarity determining regions ('CDRs') of the scFv designated MR1, but with mutations at positions 98 and 99 in the CDR3 of the heavy chain variable region and, optionally, in other CDRs. In particular, the invention provides an antibody, designated MR1-1, which mutates MR1 in the CDR3 of the VH and VL chains. The invention provides additional antibodies in which MR1 is mutated in the CDR1 and 2 of VH or VL, or both.

Anti-EGFRvIII scFvs with improved cytotoxicity and yield, immunotoxins based thereon, and methods of use thereof

Growing community of inventors

Rockville, MD, United States of America

Richard Beers