Mariusz W Szkudlinski

US Patent:

7070788, Jul 4, 2006

Filed:

Jan 25, 2002

Appl. No.:

10/057113

Inventors:

Mariusz W. Szkudlinski - Potomac MD, US
Bruce D. Weintraub - Rockville MD, US
Mathis Grossmann - Parkville, AU

Assignee:

The United States of America as represented by the Department of Health and Human Services - Washington DC

International Classification:

C07K 14/59

US Classification:

4241981, 435 694, 435325, 4352523, 4353201, 530398, 536 2351

Abstract:

The invention is directed toward a human glycoprotein hormone having at least one, two, three, four, or five basic amino acids in the α-subunit at positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20. The inventions is also directed to a human glycoprotein where at least one of the amino acids at position 58, 63, and 69 of the β-subunit of the human thyroid stimulating hormone are basic amino acids. The invention is further directed to a modified human glycoprotein hormone having increased activity over a wild-type human glycoprotein hormone, where the modified human glycoprotein comprises a basic amino acid substituted at a position corresponding to the same amino acid position in a non-human glycoprotein hormone having an increased activity over the wild-type human glycoprotein hormone. The invention is also directed to a method of constructing superactive nonchimeric analogs of human hormones comprising comparing the amino acid sequence of a more active homolog from another species to the human hormone, and selecting superactive analogs from the substituted human hormones. The invention is also directed to nucleic acids encoding the modified human glycoprotein hormones, vectors containing those nucleic acids, and host cells containing those vectors.

US Patent:

7687610, Mar 30, 2010

Filed:

Apr 21, 2006

Appl. No.:

11/409428

Inventors:

Mariusz W. Szkudlinski - Potomac MD, US
Bruce D. Weintraub - Rockville MD, US
Mathis Grossmann - Parkville, AU

Assignee:

The United States of America as represented by the Department of Health and Human Services - Washington DC

International Classification:

C07K 14/59
C07H 21/04
C12N 15/16

US Classification:

530398, 435 694, 4353201, 530850, 536 235, 536 231, 514 12, 4241981

Abstract:

The invention is directed toward a human glycoprotein hormone having at least one, two, three, four, or five basic amino acids in the α-subunit at positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20. The invention is also directed to a human glycoprotein where at least one of the amino acids at position 58, 63, and 69 of the β-subunit of the human thyroid stimulating hormone are basic amino acids. The invention is further directed to a modified human glycoprotein hormone having increased activity over a wild-type human glycoprotein hormone, where the modified human glycoprotein comprises a basic amino acid substituted at a position corresponding to the same amino acid position in a non-human glycoprotein hormone having an increased activity over the wild-type human glycoprotein hormone. The invention is also directed to a method of constructing superactive nonchimeric analogs of human hormones comprising comparing the amino acid sequence of a more active homolog from another species to the human hormone, and selecting superactive analogs from the substituted human hormones. The invention is also directed to nucleic acids encoding the modified human glycoprotein hormones, vectors containing those nucleic acids, and host cells containing those vectors.

US Patent:

8377879, Feb 19, 2013

Filed:

Jul 21, 2011

Appl. No.:

13/187956

Inventors:

Mariusz W. Szkudlinski - Rockville MD, US
Bruce D. Weintraub - Rockville MD, US

Assignee:

Trophogen, Inc. - Rockville MD

International Classification:

A61K 38/24
C07K 14/59

US Classification:

514 99, 530350, 530398

Abstract:

This invention provides superactive analogs of FSH demonstrating enhanced bioactivity both in vitro and in vivo as compared to wild type FSH. In particular, the analogs of the invention demonstrate at least a ten fold increase in potency or at least a ten percent increase in maximal efficacy as compared to wild type protein. The analogs are particularly useful in treating subjects showing low FSH receptor expression or poor FSH receptor responsiveness, and for the treatment of any condition associated with glycoprotein hormone activity.

US Patent:

8044187, Oct 25, 2011

Filed:

May 15, 2009

Appl. No.:

12/467081

Inventors:

Mariusz W. Szkudlinski - Potomac MD, US
Bruce D. Weintraub - North Potomac MD, US
Mathis Grossmann - Parkville, AU

Assignee:

The United States of America, as represented by the Secretary, Department of Health and Human Services - Washington DC

International Classification:

C07K 14/59

US Classification:

536 2351, 435 694, 435325, 4352523, 4353201, 4241981, 530398

Abstract:

The invention is directed toward a human glycoprotein hormone having at least one, two, three, four, or five basic amino acids in the α-subunit at positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20. The invention is also directed to a human glycoprotein where at least one of the amino acids at position 58, 63, and 69 of the β-subunit of the human thyroid stimulating hormone are basic amino acids. The invention is further directed to a modified human glycoprotein hormone having increased activity over a wild-type human glycoprotein hormone, where the modified human glycoprotein comprises a basic amino acid substituted at a position corresponding to the same amino acid position in a non-human glycoprotein hormone having an increased activity over the wild-type human glycoprotein hormone. The invention is also directed to a method of constructing superactive nonchimeric analogs of human hormones comprising comparing the amino acid sequence of a more active homolog from another species to the human hormone, and selecting superactive analogs from the substituted human hormones. The invention is also directed to nucleic acids encoding the modified human glycoprotein hormones, vectors containing those nucleic acids, and host cells containing those vectors.

US Patent:

20020169292, Nov 14, 2002

Filed:

Mar 20, 2001

Appl. No.:

09/813398

Inventors:

Bruce Weintraub - Rockville MD, US
Mariusz Szkudlinski - Potomac MD, US

International Classification:

A61K038/22
C07H021/04
C12P021/02
C12N005/06
C07K014/575

US Classification:

530/397000, 514/008000, 536/023500, 435/069400, 435/325000, 435/320100

Abstract:

Compositions and methods based on mutant Cystine Knot Growth Factors (CKGFs) comprising amino acid substitutions relative to the wild type hormone/growth factor. Mutated glycoprotein hormones, including thyroid stimulating hormone (TSH) and chorionic gonadotropin (CG) are disclosed as exemplary mutant CKGFs. Mutant TSH heterodimers and hCH heterodimers possessed modified bioactivities, including superagonist activity. Accordingly, the present invention provides methods for using mutant CKGFs, CKGF analogs, fragments, and derivatives thereof for treating or preventing diseases. Pharmaceutical and diagnostic compositions, methods of using mutant TSH heterodimers and TSH analogs with utility for treatment and prevention of metabolic and reproductive diseases are also provided.

US Patent:

20040265972, Dec 30, 2004

Filed:

Apr 19, 2004

Appl. No.:

10/826324

Inventors:

Bruce Weintraub - Rockville MD, US
Mariusz Szkudlinski - Potomac MD, US

International Classification:

A61K038/22
C07K014/575
C07H021/04

US Classification:

435/069400, 435/320100, 435/325000, 530/397000, 514/008000, 536/023500

Abstract:

Compositions and methods based on mutant Cystine Knot Growth Factors (CKGFs) comprising amino acid substitutions relative to the wild type hormone/growth factor. Mutated glycoprotein hormones, including thyroid stimulating hormone (TSH) and chorionic gonadotropin (CG) are disclosed as exemplary mutant CKGFs. Mutant TSH heterodimers and hCH heterodimers possessed modified bioactivities, including superagonist activity. Accordingly, the present invention provides methods for using mutant CKGFs, CKGF analogs, fragments, and derivatives thereof for treating or preventing diseases. Pharmaceutical and diagnostic compositions, methods of using mutant TSH heterodimers and TSH analogs with utility for treatment and prevention of metabolic and reproductive diseases are also provided.

US Patent:

20040266665, Dec 30, 2004

Filed:

Mar 1, 2004

Appl. No.:

10/788383

Inventors:

Bruce Weintraub - Rockville MD, US
Mariusz Szkudlinski - Potomac MD, US

International Classification:

A61K038/22

US Classification:

514/008000, 530/398000

Abstract:

The present invention is based upon the discovery that mutant subunits and mutant subunits each comprising amino acid substitutions relative to the wild type can be produced and assembled to form a mutant TSH heterodimer or TSH analog that possesses higher bioactivity in vitro and longer half life in vivo. Accordingly, the present invention provides methods for using mutant TSH heterodimers, TSH analogs, fragments, and derivatives thereof for treating or preventing diseases of the thyroid, in particular thyroid cancer. The invention also relates to methods of diagnosis, prognosis and monitoring for thyroid-related functions. Pharmaceutical and diagnostic compositions, methods of using mutant TSH heterodimers and TSH analogs with utility for treatment and prevention of metabolic and reproductive diseases are also provided.

US Patent:

20070219116, Sep 20, 2007

Filed:

Mar 18, 2005

Appl. No.:

10/593466

Inventors:

Mariusz Szkudlinski - Rockville MD, US
Bruce Weintraub - Rockville MD, US

International Classification:

A61K 38/24
C07H 21/04
C07K 14/59
C12N 15/63
C12N 5/06
C12N 5/08

US Classification:

514002000, 435320100, 435325000, 435375000, 530399000, 536023510

Abstract:

This invention provides superactive analogs of FSH demonstrating enhanced bioactivity both in vitro and in vivo as compared to wild type FSH. In particular, the analogs of the invention demonstrate at least a ten fold increase in potency or at least a ten percent increase in maximal efficacy as compared to wild type protein. The analogs are particularly useful for treating subjects showing low FSH receptor expression or poor FSH receptor responsiveness, and for the treatment of any condition associated with glycoprotein hormone activity.