Dana-Farber-Cancer Institute Inc.

Boehringer Ingelheim Pharmaceuticals, Inc.

Steven D Marlin

Robert Rothlein

Timothy Alan Springer

Michael L Dustin

Revati J Tatake

Randall Wilber Barton

The present invention relates to intercellular adhesion molecules (ICAM-1) which are involved in the process through which lymphocytes recognize and migrate to sites of inflammation as well as attach to cellular substrates during inflammation. The invention is directed toward such molecules, screening assays for identifying such molecules and antibodies capable of binding such molecules. The invention also includes uses for adhesion molecules and for the antibodies that are capable of binding them.

Functional derivatives of ICAM-1 with altered ability to bind LFA-1 or HRV

This invention relates to chimeric nucleic acids and to the therapeutic induction of apoptosis in activated inflammatory cells, or cells at a site of inflammation, by introducing into those cells the chimeric nucleic acid. The chimeric nucleic acid having at least one TNF&agr; promoter enhancer attached to a functional copy of a TNF&agr; promoter and further attached to at least one copy of an apoptosis-inducing gene, which is further attached to a 3&prime;UTR. The apoptosis-inducing gene is Granzyme B. The invention also relates to methods of making and using self-regulated apoptosis chimeric nucleic acids and pharmaceutical compositions containing them for treating inflammatory diseases.

Self-regulated apoptosis of inflammatory cells by gene therapy

This invention relates to the therapeutic induction of apoptosis in activated inflammatory cells, or cells at a site of inflammation, by introducing into those cells a chimeric gene containing an apoptosis-inducing gene (AIG) driven by a promoter of an inducible gene activated in inflammation and a promoter enhancer such that the inflammatory cells are targeted. In one embodiment, the chimeric gene comprises at least one TNF&agr; promoter enhancer attached to a functional copy of a minimal TNF&agr; promoter and further attached to at least one copy of an apoptosis-inducing gene, wherein expression of the gene is driven by the TNF&agr; promoter. Attachment can be direct, distal, proximal or combinations thereof. Example apoptosis-inducing genes include caspase 3, caspase 4, caspase 5, Granzyme B. Advantageously, the TNFp-AIG chimeric gene is expressed in only those cells producing the inflammatory cytokine, TNF&agr;. In addition, the TNFp-AIG chimeric gene also sequesters inducible TNFp transcription factors, thereby reducing endogenous production of TNF&agr;. The invention also relates to methods of making and using self-regulated apoptosis chimeric genes and pharmaceutical compositions containing them for treating inflammatory diseases.

Self-regulated apoptosis of inflammatory cells

ICAM-1 derivatives with altered ability to bind LFA-1

Soluble fragments of human intercellular adhesion molecule-1

Nucleotide sequence encoding intercellular adhesion molecule-1 and

R6-5-D6, an antibody which binds intercellular adhesion molecule-1

A method for the detection of the presence of inflammation in a patient by measuring the amount of circulating intercellular adhesion molecule (cICAM-1) in a sample of one or more bodily fluids of the patient and then comparing the amount of cICAM-1 in the sample to standards normal for the bodily fluid or fluids assayed. The amount of cICAM-1 can be measured using anti-ICAM-1 antibodies. Higher than normal amounts of cICAM-1 indicate the presence of inflammation.

Method for detecting inflammation

Method for detecting pathological pregnancy

Pharmaceutical compositions comprising antibodies to intercellular adhesion molecule-1 (ICAM-1 or CD54) are useful in methods of decreasing the severity of inflammation associated with the adhesion of leukocytes to cells bearing ICAM-1. Treatment with anti-ICAM-1 antibodies reduced the severity of inflammation associated with acute organ or tissue rejection and prolonged allograft survival time. Such compositions may optionally contain other immunsuppressive agents.

Intercellular adhesion molecules, and their binding ligands

A method for the detection of the presence of inflammation in a patient by measuring the amount of circulating intercellular adhesion molecule (cICAM-1) in a sample of one or more bodily fluids of the patient and then comparing the amount of cICAM-1 in the sample to standards normal for the bodily fluid or fluids assayed. The amount of cICAM-1 can be measured using anti-ICAM-1 antibodies. Higher than normal amounts of cICAM-1 indicate the presence of inflammation. Also contemplated is a method for the detection of organ transplant or tissue graft rejection.

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Danbury, CT, United States of America

Steven D Marlin