US2013323240A1PendingUtilityA1
Humanized antibodies against light and uses thereof
Assignee: TEVA BIOPHARMACEUTICALS USA INCPriority: Mar 24, 2009Filed: Aug 8, 2013Published: Dec 5, 2013
Est. expiryMar 24, 2029(~2.7 yrs left)· nominal 20-yr term from priority
A61P 35/02A61P 9/10A61P 37/00A61P 37/02A61P 35/00A61P 37/06A61P 25/00A61P 29/00A61P 19/02A61P 1/16C07K 16/2875A61P 1/00A61P 11/00A61P 17/06G01N 33/53C07K 2317/24C07K 2317/34A61P 1/04A61K 47/48546
47
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention is directed to antigen-binding polypeptides, or variants or derivatives thereof which specifically bind the LIGHT polypeptide. The invention is also directed to methods of making and using such antibodies specifically in the treatment or diagnosis of immune, inflammatory and malignant diseases or conditions (e.g. inflammatory bowel disease; Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis and transplantation).
Claims
exact text as granted — not AI-modified1 .- 30 . (canceled)
31 . An antigen-binding polypeptide which specifically binds to a LIGHT polypeptide, wherein the antigen-binding polypeptide comprises a humanized antibody heavy chain variable region comprising:
(a) a CDR-H1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 26)
DYYIY;
(ii)
(SEQ ID NO: 29)
TYLIE;
(iii)
(SEQ ID NO: 32)
TYWMN;
and
(iv)
(SEQ ID NO: 35)
NYLIE;
(b) a CDR-H2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 27)
YIDPYNGGTKYNQKFKD;
(ii)
(SEQ ID NO: 30)
VINPGTGETKYNENFRA;
(iii)
(SEQ ID NO: 33)
MIHPSDSESRLNQKFID;
and
(iv)
(SEQ ID NO: 36)
VINPGSGDTKYNENFKG;
and
(c) a CDR-H3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 28)
TSGSSWFPY;
(ii)
(SEQ ID NO: 31)
WDR;
(iii)
(SEQ ID NO: 34)
GNYVWAMDY;
and
(iv)
(SEQ ID NO: 37)
WNY.
32 . The antigen-binding polypeptide of claim 31 , wherein the humanized antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of:
(a)
(SEQ ID NO: 5)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIG
YIDPYNGGTKYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCAR
TSGSSWFPYWGQGTLVTVSS;
(b)
(SEQ ID NO: 6)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIG
YIDPYNGGTKYNQKFKDKATLTVDKSTSTAYMELSSLRSEDTAVYYCAR
TSGSSWFPYWGQGTLVTVSS;
(c)
(SEQ ID NO: 7)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYLIEWVRQAPGQGLEWMG
VINPGTGETKYNENFRARVTMTRDTSISTAYMELSRLRSDDTAVYYCAR
WDRWGQGTLVTVSS;
and
(d)
(SEQ ID NO: 8)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMNWVRQAPGQGLEWMG
MIHPSDSESRLNQKFIDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR
GNYVWAMDYWGQGTLVTVSS.
33 . An antigen-binding polypeptide which specifically binds to a LIGHT polypeptide, wherein the antigen-binding polypeptide comprises a humanized antibody light chain variable region comprising:
(a) a CDR-L1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 46)
RASQSISNNLH;
(ii)
(SEQ ID NO: 49)
RSSQNLVHSNGNTYFH;
(iii)
(SEQ ID NO: 52)
RASKSVSTSGYTYMH;
and
(iv)
(SEQ ID NO: 55)
RSSQSLLHSNGNTYFH;
(b) a CDR-L2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 47)
YTYQSIS;
(ii)
(SEQ ID NO: 50)
KVSNRFS;
and
(iii)
(SEQ ID NO: 53)
ITSNLES;
and
(c) a CDR-L3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 48)
QQSNRWPLT;
(ii)
(SEQ ID NO: 51)
SQSTHVPYT;
and
(iii)
(SEQ ID NO: 54)
QHSRELPYT.
34 . The antigen-binding polypeptide of claim 33 , wherein the humanized antibody light chain variable region comprises an amino acid sequence selected from the group consisting of:
(a)
(SEQ ID NO: 13)
EIVLTQSPDFQSVTPKEKVTITCRASQSISNNLHWYQQKPDQSPKLLIK
YTYQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQSNRWPLTF
GQGTKVEIKR;
(b)
(SEQ ID NO: 14)
EIVMTQSPATLSVSPGEKATLSCRASQSISNNLHWYQQKPGQAPRLLIY
YTYQSISGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSNRWPLTF
GQGTRVEIKR;
(c)
(SEQ ID NO: 15)
DVVMTQSPLSLPVTLGQPASISCRSSQNLVHSNGNTYFHWFQQRPGQSP
RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTH
VPYTFGQGTKVEIKR;
(d)
(SEQ ID NO: 16)
DIVMTQTPLSLSVTPGQPASISCRSSQNLVHSNGNTYFHWYLQKPGQSP
QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTH
VPYTFGQGTKVEIKR;
and
(e)
(SEQ ID NO: 17)
DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYTYMHWYQQKPGQPPK
LLIYITSNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREL
PYTFGQGTKVEIKR.
35 . An antigen-binding polypeptide which specifically binds to a LIGHT polypeptide, wherein the antigen-binding polypeptide comprises:
(a) a humanized antibody heavy chain variable region comprising:
(1) a CDR-H1 comprising an amino acid sequence selected from the group consisting of
(i)
(SEQ ID NO: 26)
DYYIY;
(ii)
(SEQ ID NO: 29)
TYLIE;
(iii)
(SEQ ID NO: 32)
TYWMN;
and
(iv)
(SEQ ID NO: 35)
NYLIE;
(2) a CDR-H2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 27)
YIDPYNGGTKYNQKFKD;
(ii)
(SEQ ID NO: 30)
VINPGTGETKYNENFRA;
(iii)
(SEQ ID NO: 33)
MIHPSDSESRLNQKFID;
and
(iv)
(SEQ ID NO: 36)
VINPGSGDTKYNENFKG;
and
(3) a CDR-H3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 28)
TSGSSWFPY;
(ii)
(SEQ ID NO: 31)
WDR;
(iii)
(SEQ ID NO: 34)
GNYVWAMDY;
and
(iv)
(SEQ ID NO: 37)
WNY;
and.
(b) a humanized antibody light chain variable region comprising:
(1) a CDR-L1 comprising an amino acid sequence selected from the group consisting of
(i)
(SEQ ID NO: 46)
RASQSISNNLH;
(ii)
(SEQ ID NO: 49)
RSSQNLVHSNGNTYFH;
(iii)
(SEQ ID NO: 52)
RASKSVSTSGYTYMH;
and
(iv)
(SEQ ID NO: 55)
RSSQSLLHSNGNTYFH;
(2) a CDR-L2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 47)
YTYQSIS;
(ii)
(SEQ ID NO: 50)
KVSNRFS;
and
(iii)
(SEQ ID NO: 53)
ITSNLES;
and
(3) a CDR-L3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 48)
QQSNRWPLT;
(ii)
(SEQ ID NO: 51)
SQSTHVPYT;
and
(iii)
(SEQ ID NO: 54)
QHSRELPYT.
36 . The polypeptide of claim 35 , comprising:
(a) a variable heavy chain region comprising the amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 5)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIG
YIDPYNGGTKYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCAR
TSGSSWFPYWGQGTLVTVSS;
(ii)
(SEQ ID NO: 6)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIG
YIDPYNGGTKYNQKFKDKATLTVDKSTSTAYMELSSLRSEDTAVYYCAR
TSGSSWFPYWGQGTLVTVSS;
(iii)
(SEQ ID NO: 7)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYLIEWVRQAPGQGLEWMG
VINPGTGETKYNENFRARVTMTRDTSISTAYMELSRLRSDDTAVYYCAR
WDRWGQGTLVTVSS;
and
(iv)
(SEQ ID NO: 8)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMNWVRQAPGQGLEWMG
MIHPSDSESRLNQKFIDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR
GNYVWAMDYWGQGTLVTVSS;
and
(b) a variable light chain region comprising the amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 13)
EIVLIQSPDFQSVTPKEKVTITCRASQSISNNLHWYQQKPDQSPKLLIK
YTYQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQSNRWPLTF
GQGTKVEIKR;
(ii)
(SEQ ID NO: 14)
EIVMTQSPATLSVSPGEKATLSCRASQSISNNLHWYQQKPGQAPRLLIY
YTYQSISGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSNRWPLTF
GQGTRVEIKR;
(iii)
(SEQ ID NO: 15)
DVVMTQSPLSLPVTLGQPASISCRSSQNLVHSNGNTYFHWFQQRPGQSP
RRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTH
VPYTFGQGTKVEIKR;
(iv)
(SEQ ID NO: 16)
DIVMTQTPLSLSVTPGQPASISCRSSQNLVHSNGNTYFHWYLQKPGQSP
QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTH
VPYTFGQGTKVEIKR;
and
(v)
(SEQ ID NO: 17)
DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYTYMHWYQQKPGQPPK
LLIYITSNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREL
PYTFGQGTKVEIKR.
37 . The antigen-binding polypeptide of claim 35 , wherein the antigen-binding polypeptide is selected from the group consisting of an antibody molecule, a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, and an scFv molecule.
38 . The antigen-binding polypeptide of claim 35 , wherein the antibody molecule comprises a human heavy chain constant region and a human light chain constant region.
39 . The antigen-binding polypeptide of claim 37 , wherein the antibody molecule is an IgG molecule.
40 . The antigen-binding polypeptide of claim 37 , wherein:
(a) the antigen-binding polypeptide is an scFv molecule; or (b) the antigen-binding polypeptide is a scFv HSA fusion molecule; or (c) the antigen-binding polypeptide is a Fab HSA fusion molecule.
41 . The antigen-binding polypeptide of claim 40 , wherein:
(a) the scFv molecule of claim 40 (a) comprises a polypeptide with the formula selected from the group consisting of: (i) NH2-L-VH-X-VK-COOH and (ii) NH2-L-VK-X-VH-COOH; wherein L is a leader sequence; VH is the humanized antibody heavy chain variable region; X is a linking polypeptide; and VK is the humanized antibody light chain variable region; (b) the scFv portion of the scFv HSA fusion molecule of claim 40 (b) is expressed at the N-terminus of HSA and the polypeptide has a formula selected from the group consisting of: (i) NH2-L-VH-X-VK-HSA-COOH and (ii) NH2-L-VK-X-VH-HSA-COOH, wherein L is a leader sequence; VH is the humanized antibody heavy chain variable region; X is a linking polypeptide; HSA is human serum albumin; and VK is the humanized antibody light chain variable region; (c) the scFv portion of the scFv HSA fusion molecule of claim 40 (b) is expressed at the C-terminus of HSA and the polypeptide has a formula selected from the group consisting of: (i) NH2-HSA-VH-X-VK-COOH and (ii) NH2-HSA-VK-X-VH-COOH, wherein L is a leader sequence; VH is the humanized antibody heavy chain variable region; X is a linking polypeptide; HSA is human serum albumin and VK is the humanized antibody light chain variable region; (d) the antigen-binding polypeptide of claim 40 (c), wherein the heavy chain portion of the Fab HSA fusion molecule is expressed at the N or C terminus of HSA and the polypeptide has a formula selected from the group consisting of: (i) NH2-VH-CH1-HSA-COOH and (ii) NH2-HSA-VH-CH1-COOH, wherein VH is the humanized antibody heavy chain variable region; CH1 is the constant heavy chain domain 1; and HSA is human serum albumin; or (e) the antigen-binding polypeptide of claim 40 (c), wherein the light chain portion of the Fab HSA fusion molecule is expressed at the N or C terminus of HSA and the polypeptide has a formula selected from the group consisting of: (i) NH2-VK-CK-HSA-COOH and (ii) NH2-HSA-VK-CK-COOH, wherein VK is the humanized antibody light chain variable region; CK is the constant light chain domain; and HSA is human serum albumin.
42 . The antigen-binding polypeptide of claim 35 , conjugated to a therapeutic or diagnostic agent.
43 . The antigen-binding polypeptide of claim 42 , wherein:
(a) the therapeutic agent is selected from the group consisting of a cytotoxic agent; a radioactive label; an immunomodulator; a hormone; an enzyme; an oligonucleotide; a photoactive therapeutic agent; and a combination thereof; or (b) the diagnostic agent is selected from the group consisting of a radioactive label; a photoactive diagnostic agent; an ultrasound-enhancing agent; and a non-radioactive label.
44 . The antigen-binding polypeptide of claim 35 , wherein the polypeptide binds to LIGHT with a Kd of about 108M-1 to about 1010M-1.
45 . A pharmaceutical composition comprising any of the antigen-binding polypeptides of claim 35 and a carrier.
46 . The pharmaceutical composition of claim 45 , further comprising an additional therapeutic or diagnostic agent.
47 . A method of treating or diagnosing a disease or condition comprising administering pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition comprises an antigen-binding polypeptide which specifically binds to a LIGHT polypeptide and wherein the antigen-binding polypeptide comprises:
(a) a humanized antibody heavy chain variable region comprising:
(1) a CDR-H1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 26)
DYYIY;
(ii)
(SEQ ID NO: 29)
TYLIE;
(iii)
(SEQ ID NO: 32)
TYWMN;
(iv)
(SEQ ID NO: 35)
NYLIE;
and
(v)
(SEQ ID NO: 23)
SYYIH;
(2) a CDR-H2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 27)
YIDPYNGGTKYNQKFKD;
(ii)
(SEQ ID NO: 30)
VINPGTGETKYNENFRA;
(iii)
(SEQ ID NO: 33)
MIHPSDSESRLNQKFID;
(iv)
(SEQ ID NO: 36)
VINPGSGDTKYNENFKG;
and
(v)
(SEQ ID NO: 24)
WIFPGSDITKYNEKFKG;
and
(3) a CDR-H3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 28)
TSGSSWFPY;
(ii)
(SEQ ID NO: 31)
WDR;
(iii)
(SEQ ID NO: 34)
GNYVWAMDY;
(iv)
(SEQ ID NO: 37)
WNY;
and.
(v)
(SEQ ID NO: 25)
EDYGISTYSAMDF;
and
(b) a humanized antibody light chain variable region comprising:
(1) a CDR-L1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 46)
RASQSISNNLH;
(ii)
(SEQ ID NO: 49)
RSSQNLVHSNGNTYFH;
(iii)
(SEQ ID NO: 52)
RASKSVSTSGYTYMH;
(iv)
(SEQ ID NO: 55)
RSSQSLLHSNGNTYFH;
and
(v)
(SEQ ID NO: 43)
KASQDVGTAVA;
and
(2) a CDR-L2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 47)
YTYQSIS;
(ii)
(SEQ ID NO: 50)
KVSNRFS;
(iii)
(SEQ ID NO: 53)
ITSNLES;
and
(iv)
(SEQ ID NO: 44)
WASTRHT;
and
(3) a CDR-L3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 48)
QQSNRWPLT;
(ii)
(SEQ ID NO: 51)
SQSTHVPYT;
(iii)
(SEQ ID NO: 54)
QHSRELPYT;
and
(iv)
(SEQ ID No: 45)
QQYSSYPLT;
wherein the disease or condition is selected from the group consisting of selected an inflammatory disease or condition, an immune disease or condition, a malignant disease or condition, autoimmune disease; inflammatory bowel disease (IBD); chronic obstructive pulmonary disease (COPD); arthritis; rheumatoid arthritis; multiple sclerosis; transplant rejection; graft versus host disease (GVHD); central nervous system injury; Th1-mediated intestinal diseases; Crohn's disease; psoriasis; leukemia; lymphoma; chronic lymphocytic leukemia; atherosclerosis; lung carcinoma; colon carcinoma; and hepatitis.
48 . An isolated polynucleotide encoding an antigen-binding polypeptide which specifically binds to a LIGHT polypeptide and wherein the antigen-binding polypeptide comprises:
(a) a humanized antibody heavy chain variable region comprising:
(1) a CDR-H1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 26)
DYYIY;
(ii)
(SEQ ID NO: 29)
TYLIE;
(iii)
(SEQ ID NO: 32)
TYWMN;
(iv)
(SEQ ID NO: 35)
NYLIE;
and
(v)
(SEQ ID NO: 23)
SYYIH;
(2) a CDR-H2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 27)
YIDPYNGGTKYNQKFKD;
(ii)
(SEQ ID NO: 30)
VINPGTGETKYNENFRA;
(iii)
(SEQ ID NO: 33)
MIHPSDSESRLNQKFID;
(iv)
(SEQ ID NO: 36)
VINPGSGDTKYNENFKG;
and
(v)
(SEQ ID NO: 24)
WIFPGSDITKYNEKFKG;
and
(3) a CDR-H3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 28)
TSGSSWFPY;
(ii)
(SEQ ID NO: 31)
WDR;
(iii)
(SEQ ID NO: 34)
GNYVWAMDY;
(iv)
(SEQ ID NO: 37)
WNY;
and.
(v)
(SEQ ID NO: 25)
EDYGISTYSAMDF;
and
(b) a humanized antibody light chain variable region comprising:
(1) a CDR-L1 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 46)
RASQSISNNLH;
(ii)
(SEQ ID NO: 49)
RSSQNLVHSNGNTYFH;
(iii)
(SEQ ID NO: 52)
RASKSVSTSGYTYMH;
(iv)
(SEQ ID NO: 55)
RSSQSLLHSNGNTYFH;
and
(v)
(SEQ ID NO: 43)
KASQDVGTAVA;
and
(2) a CDR-L2 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 47)
YTYQSIS;
(ii)
(SEQ ID NO: 50)
KVSNRFS;
(iii)
(SEQ ID NO: 53)
ITSNLES;
and
(iv)
(SEQ ID NO: 44)
WASTRHT;
and
(3) a CDR-L3 comprising an amino acid sequence selected from the group consisting of:
(i)
(SEQ ID NO: 48)
QQSNRWPLT;
(ii)
(SEQ ID NO: 51)
SQSTHVPYT;
(iii)
(SEQ ID NO: 54)
QHSRELPYT;
and
(iv)
(SEQ ID No: 45)
QQYSSYPLT;
49 . An isolated polynucleotide comprising a promoter sequence operably linked to the polynucleotide of claim 48 .
50 . An isolated cell transformed with the polynucleotide of claim 49 .
51 . A method of producing the antigen-binding polypeptide encoded by the polynucleotide of claim 49 comprising:
(a) culturing a cell transformed with the polynucleotide to express the encoded antigen-binding polypeptide; and
(b) recovering the antigen-binding polypeptide so expressed.Join the waitlist — get patent alerts
Track US2013323240A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.