Syntex (u.s.a.) Inc.

Conjuchem, Inc.

Advanced Proteome Therapeutics Inc.

Syntex LLC

Other

Conjuchem Biotechnologies Inc.

Redcell Canada, Inc.

Advanced Proteone Therapeutics Inc.

Cortria Corporation

Alexander Krantz

Yonghong Song

Teng Jiam Liak

Arlindo L Castelhano

Tim F Tam

Wolin Huang

Alan M Ezrin

Diana H Pliura

Robin W Spencer

Peng Yu

Arthur M Hanel

Robin Spencer

Arlindo Lucas Castelhano

Michael C Venuti

Stephen E Horne

Zhengyu Yuan

Lawrence M DeYoung

Roger A Smith

Andrzej Wilczynski

Heinz W Pauls

Jian Jeffrey Chen

Dominique P Bridon

John M Young

Darren L Holmes

Paul David Cannon

Dominique Blanchard

Grzegorz Rymarczyk

Diane DeNagel

Hal Van Wart

The present disclosure provides methods for site-selectively crosslinking payloads to antibodies and other proteins. This can be accomplished using traceless affinity labels designed to label target proteins with bio-orthogonally reactive entities (ORE) using the compositions and methods described herein.

Composition and method for modifying polypeptides

The present disclosure relates to site-selective labeling compounds, and methods of using such compounds.

Site-selective functionalization of proteins using traceless affinity labels

The present invention relates to the formation of conjugates (e.g., protein-protein dimers) using a-halo-acetophenones, benzylic halides, quinones, and related compounds as a conjugating system. The invention also features compositions that include the conjugates described herein, as well as uses of these conjugates in methods of medical treatment.

Crosslinking of proteins and other entities via conjugates of &#x3b1;-haloacetophenones, benzyl halides, quinones, and their derivatives

The present invention relates to the formation of protein conjugates from proteins chemically modified for linkage to (1) anticancer drug pharmacophores, (2) ligands to biomarkers on cancer cell surfaces, (3) and/or another protein molecule. It provides and specifies new compositions, methods and combinations for tumor, and tumor vasculature targeting and cancer treatment.

Site-specific labeling and targeted delivery of proteins for the treatment of cancer

The present invention generally provides methods for the site-specific modification of peptides, polypeptides, and proteins, e.g., granulocyte macrophage colony-stimulating factor, human superoxide dismutase, annexin, leptin, antibodies and the like, cytokines and chemokines, at their N-termini and at sites at which unnatural aminoacids have been introduced along the protein framework. The modifications described herein can be used for the synthesis and application of the adducts in radio-labeling, molecular imaging and protein therapeutic applications, and the treatment of disorders such as rheumatoid arthritis, lupus erythematosus, psoriasis, multiple sclerosis, type-1 diabetes, Crohn's disease, and systemic sclerosis, Alzheimer disease, cancer, liver disease (e.g., alcoholic liver disease), and cachexia.

Site-specific modification of proteins through chemical modification enabling protein conjugates, protein dimer formation, and stapled peptides

Site-specific modifications of proteins at their N-termini are provided. In particular, a chemical modification of proteins at their N-termini via a transamination reaction to form homogeneous adducts such as, the corresponding oxime derivatives is provided. Methods of making and using the adducts in radio-labeling, molecular imaging applications, and treatment of disorders such as cancer, Crohn's disease, arthritis, atherothrombosis and plaque rupture are also provided.

Site-specific chemical modification of proteins at their N-termini, enabling the formation of homogeneous adducts

The present invention provides methods of discovering and mapping secondary binding sites on biological molecules (e.g., proteins), the effects, if any, of site occupancy on the primary function of the molecule, and the screening of small molecules against the secondary binding sites. The invention further provides novel complexes for modification of secondary binding sites and the resulting modified biological molecules.

Tandem analyses of noncovalently driven effectors for modulatory mapping of activities of protein sites

Methods and compositions are provided for identifying compounds having affinity or complementarity to a target molecule. Compounds according to the invention may be described by the formula E-C&#x2014;R&#x2014;C-A, wherein E is a therapeutic or diagnostic agent, R is a reactive group, Cand Care connector groups between E and R and between R and A, respectively, and A is an affinity group comprising the sequence F--Y-E-E. Compounds according to the invention may be used for labeling the target molecule, particularly where the target molecule is naturally found in a complex mixture, such as a physiological fluid, like blood. By affinity labeling in vivo, the lifetime of physiologically active entities can be greatly enhanced by becoming bound to long-lived blood components. The covalently bound entity may also serve as an antagonist or agonist of a particular binding protein or as an enzyme inhibitor.

Affinity markers for human serum albumin

Methods and compositions are provided for identifying compounds having affinity to a target site. The method provides for the affinity group to be a leaving group from a reactive functionality capable of forming a covalent bond to the target site. One can combine the compound comprising the target site with the library, and assay for the resulting composition of the leaving groups. The leaving groups having the highest concentration can be identified as the groups having the binding highest affinity for the target site. The selected compounds may then be used for labeling the target molecule, particularly where the target molecule is naturally found in a complex mixture, such as a physiological fluid, like blood. By affinity labeling in vivo, the lifetime of physiologically active entities can be greatly enhanced by becoming bound to long lived blood components. The covalently bound entity may also serve as an antagonist or agonist of a particular binding proteins or as an enzyme inhibitor.

Affinity labeling libraries with tagged leaving group

Novel methods and compositions are provided for preferentially bonding an oligomeric molecule to a macromolecular target where the target is a member of a complex mixture and/or there is preferential bonding at one of a plurality of available bonding sites of the macromolecular target. The methods represent a complete system for both producing and identifying affinity label molecules from a combinatorial library which preferentially bind to a marcomolecular target or target site and preferentially binding those affinity labels to a macromolecule of interest either ex vivo or in vivo. Macromolecular targets include a variety of cellular- and non-cellular-associated proteins.

Affinity labeling libraries and applications thereof

Novel compounds comprising chemically reactive intermediates which can react with available reactive functionalities on blood components to form covalent linkages, where the resulting covalently-bound conjugates are found to have thrombin inhibition activity are provided. Specifically, the thrombin inhibitor compounds of the present invention are derivatives of the known thrombin inhibitor argatroban, which can be covalently linked to chemically reactive functionalities on various blood components. The conjugated thrombin inhibitors thereby have extended lifetimes in the bloodstream, as compared to the unconjugated parent drug, and are, therefore, capable of maintaining thrombin inhibitory activity for extended periods of time as compared to the unconjugated parent drug. Also provided herein are methods for inhibiting thrombin activity in vivo comprising administering to the bloodstream of a mammalian host the novel compounds of the present invention.

Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes

Novel compounds comprising chemically reactive intermediates which can react with available reactive functionalities on blood components to form covalent linkages, where the resulting covalently-bound conjugates are found to have renin inhibition activity are provided. Specifically, the renin inhibitor compounds of the present invention are tripeptide derivatives of a known renin inhibitor which can be covalently linked to chemically reactive functionalities on various blood components. The conjugated renin inhibitors thereby have extended lifetimes in the bloodstream, as compared to the unconjugated parent drug, and are, therefore, capable of maintaining renin inhibitory activity for extended periods of time as compared to the unconjugated parent drug. Also provided herein are methods for inhibiting renin activity in vivo comprising administering to the bloodstream of a mammalian host the novel compounds of the present invention.

Extended lifetimes in vivo renin inhibitors

Compounds of formula (I): ##STR1## as single stereoisomers or mixtures thereof and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as interstitial collagenases, and are useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteases, for example arthritic diseases or bone resorption disease, such as osteoporosis.

Matrix metalloprotease inhibitors

Methods for producing novel conjugates of thrombin inhibitors

Methods and compositions for producing novel conjugates of thrombin

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Boston, MA, United States of America

Alexander Krantz