La Jolla Pharmaceutical Company

Neorx Corporation

La Jolla Pharmaceutial Company

David S Jones

Stephen M Coutts

Douglas Alan Livingston

Lin Yu

Ananthachari Srinivasan

Alan R Fritzberg

Michael J Conrad

John P Hachmann

David Matthew Marquis

Edward Jess Victoria

Sudhakar Kasina

John M Reno

Linda M Gustavson

Jeffrey N Fitzner

Daniel S Wilbur

Paul A Barstad

G Michael Iverson

Gilbert M Iverson

Matthew D Linnik

Richard M Jack

Chemically-defined, non-polymeric valency platform molecules and conjugates comprising chemically-defined valency platform molecules and biological or chemical molecules including polynucleotide duplexes of at least 20 base pairs that have significant binding activity for human lupus anti-dsDNA autoantibodies.

Chemically defined non-polymeric valency platform molecules and conjugates thereof

Chemically-defined non-polymeric valency platform molecules and conjugates thereof

Valency platform molecules comprising high molecular weight polyethylene oxide groups are provided, as well as conjugates thereof with biologically active molecules, and methods for their preparation. The high molecular weight polyethylene oxide group has, for example, a molecular weight of greater than 22,000 Daltons, for example at least 40,000 Daltons. In one embodiment, a composition comprising the valency platform molecules is provided, wherein the molecules have a polydispersity less than about 1.2. Conjugates of the valency platform molecule and a biologically active molecule, such as a saccharide, poly(saccharide), amino acid, poly(amino acid), nucleic acid or lipid also are provided. Also provided are pharmaceutically acceptable compositions comprising the conjugates disclosed herein and a pharmaceutically acceptable carrier, as well as methods of making and using the conjugates and compositions.

Multivalent platform molecules comprising high molecular weight polyethylene oxide

The present invention provides domain 1 &#x3b2;GPI polypeptides, polynucleotides encoding these polypeptides, mimetics of these polypeptides, and methods using domain 1 &#x3b2;GPI polypeptides and mimetics. Domain 1 of &#x3b2;GPI has been shown to bind to anti-cardiolipin (&#x3b2;GPI-dependent antiphospholipid) antibodies, which are associated with several pathologies, such as thrombosis and fetal loss. The domain 1 &#x3b2;GPI polypeptides may be used to detect &#x3b2;GPI-dependent antiphospholipid antibodies in a sample. The invention further provides methods of inducing tolerance using these domain 1 &#x3b2;GPI polypeptides.

Therapeutic and diagnostic domain 1 &#x3b2;2GPI polypeptides and methods of using same

This invention pertains generally to valency molecules, such as valency platform molecules which act as scaffolds to which one or more molecules may be covalently tethered to form a conjugate. More particularly, the present invention pertains to valency platform molecules which comprise a carbamate linkage (i.e., &mdash;O&mdash;C(&boxH;O)&mdash;N<). In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae I, II, or III, shown in FIG. . In one aspect, the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae IV, V, or VI, shown in FIG. . The present invention also pertains to methods of preparing such valency platform molecules, conjugates comprising such valency platform molecules, and methods of preparing such conjugates.

Valency platform molecules comprising carbamate linkages

aPL analogs that (a) bind specifically to B cells to which an aPL epitope binds and are disclosed. Optimized analogs lack T cell epitope(s) are useful as conjugates for treating aPL antibody-mediated diseases. Conjugates comprising aPL analogs and nonimmunogenic valency platform molecules are provides as are novel nonimmunogenic valency platform molecules and linkers. Methods of preparing and identifying said analogs, methods of treatment using said analogs, methods and compositions for preparing conjugates of said analogs and diagnostic immunoassays for aPL antibodies are disclosed.

APL immunoreactive peptides, conjugates thereof and methods of treatment for APL antibody-mediated pathologies

This invention provides conjugates useful for xenotransplantation which comprise a galactose &agr;1,3 galactosyl (&agr;Gal) epitope conjugated to a valency platform molecule, preferably a chemically defined valency platform molecule which allows precise valency. The invention also provides compositions comprising these conjugates, and methods (such as methods for inducing tolerance) using these conjugates and compositions.

Conjugates comprising galactose &agr;1,3 galactosyl epitopes and methods of using same

aPL analogs that (a) bind specifically to B cells to which an aPL epitope binds and are disclosed. Optimized analogs lack T cell epitope(s) are useful as conjugates for treating aPL antibody-mediated diseases. Methods of preparing and identifying said analogs, methods of treatment using said analogs, methods and compositions for preparing conjugates of said analogs and diagnostic immunoassays for aPL antibodies are disclosed.

aPL immunoreactive peptides, conjugates thereof and methods of treatment for aPL antibody-mediated pathologies

Conjugates of nonimmunogenic valency platform molecules and analogs of immunogens that possess the specific B cell binding ability of the immunogen but lack T cell epitopes and which, when introduced into individuals, induce humoral anergy to the immunogen are disclosed. Accordingly, these conjugates are useful for treating antibody-mediated pathologies that are caused by foreign or self immunogens.

Composition for inducing humoral anergy to an immunogen comprising a T

Phosphoramidites of the formula ##STR1## where R is a base-labile protecting group, R.sup.1 and R.sup.2 are individually alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or aryl of 6 to 20 carbon atoms or are joined together to form with the nitrogen atom a cyclic structure of 4-7 carbon atoms and 0 to 1 annular chalcogen atoms of atomic number 8 to 16, G is a hydrocarbylene group of 1 to 20 carbon atoms and Z is a hydroxy-protected vicinal diol group bound to G by one of the vicinal diol carbon atoms or a disulfide group and bound to G by one of the sulfur atoms of the disulfide group, with the proviso that G is of at least 4 carbon atoms when Z is said disulfide group are used in conventional automated oligonucleotide synthesis to introduce a functional aldehyde or thiol group on the 5' end of the oligonucleotide to thereby provide a reactive site on the oligonucleotide that may be used to conjugate the oligonucleotide to molecules that contain a free amino group or an electrophilic center reactive with a thiol group.

Modified phosphorous intermediates for providing functional groups on

Chemically-defined non-polymeric valency platform molecules and

The present invention provides metal chelating compounds, to chelates and chelate-targeting agent conjugates formed from the chelating compounds, and to methods for making and using these compositions. The chelating compounds incorporate two nitrogen atoms and three sulfur atoms ('N.sub.2 S.sub.3 '), two nitrogen atoms and four sulfur atoms ('N.sub.2 S.sub.4 '), or three nitrogen atoms and three sulfur atoms ('N.sub.3 S.sub.3 '). Metals, and metal oxides, capable of being chelated by the compounds include those that are radionuclides, such as .sup.99m Tc and .sup.186/188 Re. The targeting agent portion of the chelate-targeting agent conjugates provided includes antibodies, peptides, hormones, enzymes and biological response modifiers. Methods for making the conjugates are provided and encompass the addition of a metal, or metal oxide, to a chelating compound prior to attachment to a targeting agent as well as subsequent to the attachment. Another aspect of the invention provides kits for producing chelate-targeting agent conjugates for radiopharmaceutical use. An additional aspect of the invention provides methods for using the chelate-targeting agent conjugates for diagnostic and therapeutic purposes, such as detection of a target site and delivery of a radionuclide to the site, respectively.

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San Diego, CA, United States of America

David S Jones