La Jolla Cancer Research Foundation

La Jolla Cancer Research Center

Phillips Petroleum Company

Research Corporation Technologies, Inc.

Integra Lifesciences Corporation

Juerg F Tschopp

Soan Cheng

Michael D Pierschbacher

William S Craig

Daniel G Mullen

Ronald Ingram

Michael Miller Harpold

David S Lukeman

Steven B Ellis

David W Stroman

Paul F Brust

Thomas R Gingeras

James M Cregg

Gregory P Thill

Kotikanyadan Sreekrishna

Russell A Brierley

Richard G Buckholz

Kathryn A Barr

Ralph-Heiko Mattern

Timothy Irvin Malaney

Fred Cahn

Kotikanyad Sreekrishna

Compositions of cross-linked collagen and a glycosaminoglycan are provided which retain characteristics rendering them useful as tissue engineering matrices or scaffolds following terminal sterilization. Also provided are methods for producing these compositions and terminally sterilized matrices or scaffolds from these compositions as well as methods of using these matrices or scaffolds as tissue engineering devices.

Collagen/glycosaminoglycan matrix stable to sterilizing by electron beam radiation

The invention provides cyclic peptides which inhibit platelet aggregation without causing prolonged bleeding time. The invention provides RGD or KGD containing peptides which are cyclized and contain hydrophobic amino acids adjacent to the carboxy terminus of the RGD sequence. Peptides of this nature are also provided which contain in addition to the hydrophobic amino acid an adjacent positively charged amino acid. Such peptides have a high affinity for the receptor IIb/IIIa and a low affinity for the fibronectin and vitronectin receptors. Such peptides can be administered in a suitable physiologically acceptable carrier to therapeutically treat thrombosis.

Method and composition for treating thrombosis

The invention provides cyclic peptides which inhibit platelet aggregation without causing prolonged bleeding time. The invention provides RGD or KGD containing peptides which are cyclized and contain hydrophobic moieties adjacent to the carboxy terminus of the RGD sequence. Peptides of this nature are also provided which contain in addition to the hydrophobic. moiety an adjacent positively charged moiety. Such peptides have a high affinity for the receptor IIb/IIIa and a low affinity for the fibronectin and vitronectin receptors. Such peptides can be administered in a suitable physiologically acceptable carrier to therapeutically treat thrombosis.

The present invention provides Arg-Gly-Asp peptides that can alter the binding of osteoclasts to a matrix such as bone or can selectively alter integrin receptor binding. The invention also provides methods of using the Arg-Gly-Asp peptides to alter .alpha..sub.v .beta..sub.3 integrin receptor-mediated binding of a cell such as an osteoclast, endothelial cell or smooth muscle cell to a matrix. The invention further provides methods for ameliorating the severity of a pathology characterized, in part, by an undesirable level of bone resorption, angiogenesis or restenosis in a subject.

Peptides for altering bone resorption, angiogenesis and restenosis

The present invention provides Arg--Gly--Asp peptides that can alter the binding of osteoclasts to a matrix such as bone or can selectively alter integrin receptor binding. The invention also provides methods of using the Arg--Gly--Asp peptides to alter .alpha..sub.V .beta..sub.3 integrin receptor-mediated binding of a cell such as an osteoclast, endothelial cell or smooth muscle cell to a matrix. The invention further provides methods for ameliorating the severity of a pathology characterized, in part, by an undesirable level of bone resorption, angiogenesis or restenosis in a subject.

Peptides useful for altering bone resorption

Use of peptides for altering bone resorption

A method for identifying a peptide useful for inhibiting platelet aggregation activity without substantially prolonging bleeding time comprising determining the IC.sub.50 value of the peptide in both a heparin assay and a citrate assay and then comparing the value of the IC.sub.50 from each assay.

The present invention provides Arg--Gly--Asp peptides that can alter the binding of osteoclasts to a matrix such as bone or can selectively alter integrin receptor binding. The invention also provides methods of using the Arg--Gly--Asp peptides to alter .alpha..sub.v .beta..sub.3 integrin receptor-mediated binding of a cell such as an osteoclast, endothelial cell or smooth muscle cell to a matrix. The invention further provides methods for ameliorating the severity of a pathology characterized, in part, by an undesirable level of bone resorption, angiogenesis or restenosis in a subject.

Use of peptides for altering .alpha..sub.V .beta..sub.3 -mediated binding

The present invention provides Arg-Gly-Asp peptides that can reduce or inhibit the binding of osteoclasts to a matrix such as bone or can selectively alter integrin receptor binding. The invention also provides methods of using the Arg-Gly-Asp peptides to reduce or inhibit osteoclast binding to a matrix, to reduce or inhibit bone resorption in a subject and to alter .alpha..sub.V .beta..sub.3 binding.

Peptides for reducing or inhibiting bone resorption

Peptides useful for altering .alpha..sub.v .beta..sub.3 -mediated binding

The present invention is directed to expression cassettes comprising a 5' regulatory region from at least one of the Pichia pastoris AOXI gene, p40 gene, DASI gene or HIS4 gene, operably linked to an HSA structural gene including the HSA signal sequence. The HSA structural gene has a translational start codon within 0 to 11 deoxyribonucleotides from the 5' end of the HSA structural gene and is operably linked to a 3' termination sequence. Further, the adenine and thymine content of the intervening deoxyribonucleotides is in the range from about 55 to about 64%. The expression cassette may be an autonomously replicating vector or an integrative vector. Other embodiments of the present invention include Pichia pastoris strains transformed with the HSA expression cassettes and processes for secretion of HSA using the expression cassettes.

Expression of human serum albumin in Pichia pastoris

The invention provides cyclic peptides which inhibit platelet aggregation without causing prolonged bleeding time. The invention provides RGD or KGD containing peptides which are cyclized and contain hydrophobic moieties adjacent to the carboxy terminus of the RGD sequence. Peptides of this nature are also provided which contain in addition to the hydrophobic moiety an adjacent positively charged moiety. Such peptides have a high affinity for the receptor IIb/IIIa and a low affinity for the fibronectin and vitronectin receptors. Such peptides can be administered in a suitable physiologically acceptable carrier to therapeutically treat thrombosis.

Novel DNA constructs comprising regulatory regions plus the structural coding region for hepatitis B surface antigen (HBsAg) are disclosed. The regulatory regions employed are responsive to methanol, non-catabolite repressing carbon sources and catabolite repressing carbon sources followed by carbon source starvation. The novel constructs are incorporated into a variety of linear and circular plasmids. Such plasmids are used to transform suitable hosts and ultimately used for the production and isolation of hepatitis B surface antigen in high yields.

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San Diego, CA, United States of America

Juerg F Tschopp