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

National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America As Represented by the Secretary of

Cetus Corporation

Other

Richard J Youle

David M Neville

Virginia G Johnson

Walter J Laird

Wojciech J Ardelt

Susanna M Rybak

Dianne L Newton

Peter J Nicholls

Larry Greenfield

Gary J Murray

Veena M Vasandani

Yon-Neng Wu

Ester Boix

YouNeng Wu

R John Collier

Mark Hallett

Marinos C Dalakas

Liu Xiuhuai

Naoshi Hagihara

David M Neville Jr

Jonathan S Hott

Compositions and methods for treatment of focal muscle spasms. Immunotoxin conjugates comprise a toxin conjugated to an antibody reactive to a muscle specific antigen.

Immunotoxin (mAB-RICIN) for the treatment of focal movement disorders

Apoptosis-modifying fusion polypeptides, and the corresponding nucleic acid molecules, are disclosed. Pharmaceutical compositions comprising these polypeptides, and the use of these polypeptides to modify apoptosis are also provided.

Receptor-mediated uptake of an extracellular BCL-xL fusion protein inhibits apoptosis

Vascular damage has proven to be dose limiting in administering immunotoxins into the brain to treat brain tumors. Vascular toxicity of immunotoxins which rely in part on exposure to lowered pH in cellular endosomes and lysosomes can be avoided by administering an endosome pH-raising agent systemically during some or all of the time that the immunotoxin is present in the brain of the organism. Suitable endosome pH-raising agents include lysosomotrophic amines, proton ionophores, and vacuolar H&plus; ATPase inhibitors. The invention increases the therapeutic window of the immunotoxins and increases the likelihood the treatment will have an effect on the course of the tumor.

Methods of protecting vasculature from damage by diphtheria toxin-and pseudomonas toxin-based immunotoxins during therapy

The present invention provides recombinant Onc (rOnc) compositions and methods. Recombinant Onc proteins of the invention have an amino terminal methionine and comprise an Onc polypeptide. The amino terminal methionine of the protein allows for recombinant production in a bacterial host cell. Cleaving the amino terminal methionine exposes the amino terminal glutamine of the polypeptide. The Onc polypeptide has an amino terminal glutamine. Cyclization of the amino terminal glutamine of the polypeptide to a pyroglutamyl residue provides rOnc polypeptides and proteins have anti-cancer and anti-viral activity.

Mutant form of a cytotoxic ribonucleolytic protein which allows production by recombinant methods

Mutant form of cytotoxic ribonucleolytic protein which allows production by recombinant methods

The present invention relates to compositions of retinoids plus immunotoxins. More particularly this invention relates to the use of retinoids to potentiate the activity of immunotoxins for treatment of mammalian diseases.

Composition of immunotoxins and retinoids and use thereof

The present invention relates to a selective cytotoxic RNase reagent. The reagent comprises a toxic moiety that is an RNase linked to a recognition moiety that binds a specific cell surface marker. Binding of the recognition moiety to a surface marker on a cell allows the toxic moiety to selectively kill the cell. To reduce immunogenicity, preferably the toxic moiety and the recognition moiety of the conjugate are endogenous to the species in which the reagent is intended for use. Cytotoxic reagents intended for use in humans preferably have as the toxic moiety a human ribonuclease, such as angiogenin, and as the recognition moiety as humanized chimeric antibody. The human ribonuclease and chimeric antibody preferably form a fused protein. The present invention also relates to pharmaceutical compositions including the cytotoxic reagent as well as treatment methods involving the use of the cytotoxic reagent.

Selective RNase cytotoxic reagents

A potent and specific immunotoxin is prepared by coupling an inactivated diphtheria toxin to a binding moiety such as a monoclonal antibody or transferrin. The immunotoxins are specific for human tumors and leukemias and are indistinguishable in cell toxicity from that of the native toxin linked to the binding domain without the toxicity to other cells. The immunotoxin is useful in treating graft versus host disease as well as selectively killing tumor cells, such as medulloblastoma and glioblastoma cells.

Mutant diphtheria toxin conjugates

Potent and specific immunotoxins are prepared by conjugation of moieties binding to receptors on the surface of tumor cells to a mutant diphtheria toxin having A-chain translocation activity, but lacking membrane-binding activity. The immunotoxins are used to treat primary tumors of neurologic origin, metastatic tumors of small cell lung carcinoma or breast carcinoma origin, leptomeningeal leukemia and leptomeningeal carcinomatosis. The preferred route of administration of the immunotoxin is to a compartment of the body containing cerebrospinal fluid.

Treatment of tumors of the central nervous system with immunotoxins

A potent and specific immunotoxin is prepared by coupling a binding-site inactivated diphtheria toxin (CRM 107) to a new binding moiety consisting of transferrin or a monoclonal antibody against the human transferrin receptor. These immunotoxins are tumor specific and lack the nonspecific toxicity produced by the binding activity of the native toxin. The immunotoxin is useful in treating primary brain tumors, metastatic tumors to the brain, CSF-borne tumors, leptomeningeal leukemia and leptomeningeal carcinomatosis.

Immunotoxins for treatment of intracranial lesions and as adjunct to

A potent and specific immunotoxin is prepared by coupling an inactivated diphteria toxin to a binding moiety such as a monoclonal antibody or transferrin. The immunotoxins are specific for human tumors and leukemias and are indistinguishable in cell toxicity from that of the native toxin linked to the binding domain without the toxicity to other cells. The immunotoxin is useful in treating graft versus host disease as well as selectively killing tumor cells, such as medulloblastoma and glioblastoma cells.

Method of preparing diphtheria immunotoxins

The rate of protein synthesis inhibition is significantly increased by adding excess ricin B chain to target cells independent of the amount of ricin A chain bound to the cell surface membrane. Ricin is a known toxin from albumin of the castor oil bean and contains an A chain and a B chain for binding to receptors. The present invention is concerned with ricin hybrids such as OX-7-ricin A chain and 19E12-F(ab) ricin A chain which were produced by conjugation of the ricin A chains with anti-Thy 1.1 monoclonal antibodies. The conjugates were utilized in pharmaceutical amounts in mice.

Inactivating protein synthesis by incubating anti-Thy 1.1-ricin a chain

A reagent and the protocol for the treatment of Graft Versus Host Disease is disclosed. Monoclonal antibodies specific for T-lymphocytes in human donor bone marrow are covalently linked to separate ricin toxin, combined in a mixture to form a treatment reagent, and combined with bone marrow removed from a human donor. The bone marrow-reagent mixture is then infused into an irradiated recipient. This protocol virtually eliminates T-lymphocyte activity, the cause of Graft Versus Host Disease.

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Garrett Park, MD, United States of America

Richard J Youle