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

Other

Novartis Ag

The UAB Research Foundation (the University of Alabama at Birmingham)

Wisconsin Alumni Research Foundation

The United States of America As Represented by the Secretary of

Scott & White Healthcare

Angimmune, LLC

David M Neville

Richard J Youle

Jung-Hee Woo

Jerry Todd Thompson

Huaizhong Hu

Shenglin Ma

Mary Ellen Digan

Jonathan Mark Hexham

Joshua E Scharff

Gary J Murray

Stuart Knechtle

Yuan-Yi Liu

Jon Asher Wolff

Arthur E Frankel

Jue Wang

Stuart J Knechtle

Kasturi Srinivasachar

Judith T Thomas

Francis T Thomas

Judith M Thomas

Methods of modulating the immune systems of patients suffering from cancers that do not bear, or do not uniformly bear, surface CD3 are provided. The methods involve administering an anti-CD3 immunotoxin (e.g. A-dmDT390-bisFv(UCHT1)), to the patient so as to cause the patient's immune system to recognize and destroy non-CD3 cancer cells.

Immunomodulation by anti-CD3 immunotoxins to treat cancers bearing or not uniformly bearing surface CD3

Provided are methods and compositions related to diphtheria toxin diabody immunotoxins.

Fold-back diabody diphtheria toxin immunotoxin and methods of use

The present invention described and shown in the specification and drawings provides novel recombinant DT-based immunotoxins, and, more specifically anti-T cell immunotoxin fusion proteins. Also provided are immunotoxins that can be expressed in bacterial, yeast, or mammalian cells. The invention also provides means for expression of the immunotoxin fusion protein. It is emphasized that this abstract is provided to comply with the rules requiring an abstract that will allow a searcher or other reader to quickly ascertain the subject matter of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

Immunotoxin fusion proteins and means for expression thereof

The present invention relates to a method of expressing an immunotoxin instrain mutated to toxin resistance comprising a) growing thein a growth medium comprising an enzymatic digest of protein and yeast extract and maintaining a dissolved oxygen concentration at 40% and above; and b) performing methanol induction with a limited methanol feed of 0.5-0.75 ml/min/IO L of initial volume during induction along with a continuous infusion of yeast extract at a temperature below 17.5&#xb0; C., antifoaming agent supplied up to 0.07%, agitation reduced to 400 RPM, and the induction phase extended out to 163 h.

Methods for expression and purification of immunotoxins

The present invention described and shown in the specification and drawings provides novel recombinant DT-based immunotoxins, and, more specifically anti-T cell immunotoxin fusion proteins. Also provided are immunotoxins that can be expressed in bacterial, yeast, or mammalian cells. The invention also provides means for expression of the immunotoxin fusion protein.

Provided is a method of treating an autoimmune disease in an animal comprising administering to the animal an antibody-DT mutant immunotoxin which routes by the anti-CD3 pathway, or derivatives thereof, under conditions such that the autoimmune disease is treated. In a further embodiment, the invention provides a method of treating T cell leukemias or lymphomas in an animal comprising administering to the animal an antibody-DT mutant immunotoxin which routes by the anti-CD3 pathway, or derivatives thereof, under conditions such that the T cell leukemias or lymphomas are treated.

Immunotoxin with in vivo T cell suppressant activity and methods of use

The invention provides a method of treating diabetes in a subject, comprising administering to the diabetic subject an immunotoxin, thereby reducing the subject's T-cell population, and administering to the subject pancreatic islet cells from a donor. The immune tolerance inducing treatment regimen, used optionally with adjunct immunosuppressive agents, prevents pancreatic islet cell rejection while maintaining long term islet cell function following xenogeneic and allogeneic pancreatic islet cell transplantation. Thus, the methods of the present invention provide a means for treating diabetes, wherein the need for exogenous insulin or immunosuppressive agents is decreased or eliminated. Also provided is a method of inhibiting a rejection response of a transplant recipient, comprising administering an immunotoxin during the peritransplant period, thereby transiently reducing the number of T-cell lymphocytes and promoting long-term survival of the transplant.

Use of immunotoxins to induce immune tolerance to pancreatic islet transplantation

Provided is a method of treating an immune system disorder not involving T cell proliferation, comprising administering to the animal an immunotoxin comprising a mutant diphtheria toxin moiety linked to an antibody moiety which routes by the anti-CD3 pathway, or derivatives thereof under conditions such that the disorder is treated. Thus, the present method can treat graft-versus-host disease. Also provided is a method of inhibiting a rejection response by inducing immune tolerance in a recipient to a foreign mammalian donor tissue or cells, comprising the steps of: a) exposing the recipient to an immunotoxin so as to reduce the recipients's peripheral blood T-cell lymphocyte population by at least 80%, wherein the immunotoxin is anti-CD3 antibody linked to a diphtheria protein toxin, wherein the protein has a binding site mutation; and b) transplanting the donor cells into the recipient, whereby a rejection response by the recipient to the donor organ cell is inhibited, and the host is tolerized to the donor cell.

Methods of inducing immune tolerance using immunotoxins

Provided are novel DT- and ETA-based immunotoxins and a method of treating an immune system disorder not involving T cell proliferation, comprising administering to the animal an immunotoxin comprising a mutant diphtheria toxin moiety linked to an antibody moiety which routes by the anti-CD3 pathway, or derivatives thereof under conditions such that the disorder is treated. Thus, the present method can treat graft-versus-host disease. Also provided is a method of inhibiting a rejection response by inducing immune tolerance in a recipient to a foreign mammalian donor tissue or cells, comprising the steps of: a) exposing the recipient to an immunotoxin so as to reduce the recipients' peripheral blood T-cell lymphocyte population by at least 80%, wherein the immunotoxin is anti-CD3 antibody linked to a diphtheria protein toxin, wherein the protein has a binding site mutation; and b) transplanting the donor cells into the recipient, whereby a rejection response by the recipient to the donor organ cell is inhibited, and the host is tolerized to the donor cell.

Immunotoxins and methods of inducing immune tolerance

Disclosed is a method of inhibiting a rejection response by a primate to a transplanted organ. One exposes the primate to a mutant diphtheria toxin linked to anti-CD3 antibody so as to largely eliminate the host's peripheral blood T cell lymphocyte population. At the same time as, or after, the exposure step one administers to the primate's thymus gland donor lymphocytes. Transplantation of the organ follows. The primate is tolerized to the transplanted organ.

Thymus tolerance in primates

In one embodiment, the invention provides a method of treating an autoimmune disease in an animal comprising administering to the animal an antibody-CRM9 conjugate which routes by the anti-CD3 pathway, or derivatives thereof, under conditions such that the autoimmune disease is treated. In another embodiment, the invention provides an anti-V.beta.-CRM9 immunoconjugate. In a further embodiment, the invention provides a method of treating T cell leukemias or lymphomas in an animal comprising administering to the animal an antibody-CRM9 conjugate which routes by the anti-CD3 pathway, or derivatives thereof, under conditions such that the T cell leukemias or lymphomas are treated.

The present invention relates to an immunotoxin. The invention further relates to a method of treating T cell leukemias and lymphomas, graft-versus-host diseases, and autoimmune diseases by administering an immunotoxin.

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Bethesda, MD, United States of America

David M Neville