Novel Chimeric Proteins and Methods for Using The Same

• US 20130243697A1
• Filed: 04/17/2012
• Published: 09/19/2013
• Est. Priority Date: 01/03/2000
• Status: Abandoned Application

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Tykocinski, Mark L., Huang, Jui-Han
• Application Number:
  US13/448,852
• Publication Number:
  US 20130243697A1
• Time in Patent Office: Days
• US Class Current: 424/9.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 14/70539 MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• CPC Class Codes: C07K 14/70578 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Novel chimeric proteins are disclosed. The proteins comprise at least two portions. The first portion binds to a first cell and decreases the cell'"'"'s ability to send a trans signal to a second cell; the second portion sends its own trans signal to the second cell. Methods for making and using these proteins in the treatment of cancer, viral infections, autoimmune and alloimmune diseases are also disclosed, as are pharmaceutical formulations comprising the novel chimeric proteins and genes. Either the proteins themselves or a genetic sequence encoding the protein can be administered. Other methods are also disclosed in which two molecular components result in decrement of a first trans signal from a first cell and the conferring of a second trans signal to a second cell.

Claims

1. A chimeric protein comprising:

a first protein that binds to at least one surface molecule on a first cell and results in the decrement of a first trans signal from said cell; and

a second protein that binds to at least one surface molecule on a second cell and sends a second trans signal to said second cell, wherein the first and second trans signals sent from the surface of said first and second cells are not the same, and wherein the first protein is selected from the group consisting of Fas, DcR3, TGF-β

, MIS, HGF, scFv, and wherein the second protein is selected from the group consisting of B7-1, B7-2, B7-h, CD40L, CD30L, OX-40L, 4-1BBL, CD70, ICAM-1, ICAM-2, ICAM-3, LFA-3, HAS, LIGHT, SLAM, lymphotoxin, TRANCE, c-KitL/SCF, IL-3, and GM-CSF.

2. The chimeric protein of claim 1, wherein the first protein effects decrement by direct masking of a trans signal of the first cell.

3. The chimeric protein of claim 1, wherein the first protein effects decrement by indirect masking of a trans signal of the first cell.

4. The chimeric protein of claim 3, wherein said indirect masking is by allosteric inhibition.

5. The chimeric protein of claim 3, wherein said indirect masking is by disruption of functional multi-molecular trans signaling complexes.

6. The chimeric protein of claim 3, wherein said indirect masking is by functional modification of the first signal by intracellular signaling.

11. The protein of claim 1, wherein said scFv is selected from the group consisting of scFv with specificity for HER-2/neu, CEA, PSA, CD33 and AIRM1.

17. The protein of claim 1, further comprising an epitope tag.

18. The protein of claim 17, wherein said epitope tag is a polyhistidine tag.

23. A pharmaceutical formulation comprising the chimeric protein of claim 1 in a suitable pharmaceutical carrier, wherein said pharmaceutical formulation is administered in unit dosage form to a patient in need thereof in therapeutically effective amounts.

24. A method for treating a patient for an illness comprising administering to said patient an effective amount of the chimeric protein of claim 1.

25. The method of claim 24, wherein said illness is selected from the group consisting of cancer, viral infection, autoimmune disease and alloimmune disease.

26. The method of claim 24, wherein said chimeric protein modifies signaling between endothelial cells and platelets.

27. The method of claim 24, wherein said chimeric protein modifies signaling between bone marrow stromal cells and other marrow elements or hematopoietic progenitors.

28. The method of claim 24, wherein said chimeric protein modifies signaling between tumor cells of a given tumor.

29. A method for treating a patient for an illness comprising administering to said patient an effective amount of a genetic sequence encoding a chimeric protein according to claim 1.

33. A method for studying an illness in an animal model comprising administering the chimeric protein of claim 1, or a gene sequence encoding the same, to said animal.

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