Humanized antibodies and compositions for binding sphingosine-1-phosphate

• US 8,222,373 B2
• Filed: 10/24/2008
• Issued: 07/17/2012
• Est. Priority Date: 10/27/2006
• Status: Active Grant

• Current Assignee: Apollo Endosurgery, Inc. (Boston Scientific Corporation)
• Original Assignee: Lpath Inc. (Boston Scientific Corporation)
• Inventors: Sabbadini, Roger A., Garland, William A., Hansen, Genevieve, Jones, Steven Tarran, Williams, David Gareth
• Primary Examiner(s): Gussow, Anne M.
• Application Number:
  US12/258,346
• Publication Number:
  US 20090130099A1
• Time in Patent Office: 1,362 Days
• Field of Search: None
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]

Abstract

The present invention relates to anti-S1P agents, particularly humanized monoclonal antibodies (and antigen binding fragments thereof) specifically reactive with S1P, compositions containing such antibodies (or fragments), and the use of such antibodies (or fragments), for example, to treat diseases and conditions associated with aberrant levels of S1P.

Claims

1. An isolated humanized antibody that binds sphingosine-1-phosphate and comprises two heavy chains and two light chains, wherein:

A. each heavy chain comprises a heavy chain variable domain comprising;

(i) a sequence of amino acid residues having an amino acid sequence EVQLVQSGAEVKKPGESLKISCQSFGYIFIDHTIHWMRQMPGQGLE WMGAISPRHDITKYNEMFRGQVTISADKSSSTAYLQWSSLKASDT AMYFCARGGFYGSTIWFDFWGQGTMVTVSS (SEQ ID NO;

32, residues 20-140, inclusive);

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of A(i), above, provided that in any event the heavy chain variable domain comprises a first complementarity determining region (CDR) comprising a sequence of amino acid residues DHTIH (SEQ ID NO;

     13), a second CDR comprising a sequence of amino acid residues AISPRHDITKYNEMFRG (SEQ ID NO;

     31), and a third CDR comprising a sequence of amino acid residues GGFYGSTIWFDF (SEQ ID NO;

     15); and

B. each light chain comprises a light chain variable domain comprising;

(i) a sequence of amino acid residues having an amino acid sequence ETTVTQSPSFLSASVGDRVTITCITTTDIDDDMNWFQQEPG KAPKLLISEGNILRPGVPSRFSSSGYGTDFTLTISKLQPEDF ATYYCLQSDNLPFTFGQGTKLEIK (SEQ ID NO;

33, residues 21-127, inclusive);

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of B(i), above, provided that in any event the light chain variable domain comprises a first CDR comprising a sequence of amino acid residues ITTTDIDDDMN (SEQ ID NO;

     10), a second CDR comprising a sequence of amino acid residues EGNILRP (SEQ ID NO;

     11), and a third CDR comprising a sequence of amino acid residues LQSDNLPFT (SEQ ID NO;

     12).

2. An isolated humanized antibody according to claim 1, wherein:

A. each heavy chain comprises a sequence of amino acid residues having an amino acid sequence;

(i) EVQLVQSGAEVKKPGESLKISCQSFGYIFIDHTIHWMRQM PGQGLEWMGAISPRHDITKYNEMFRGQVTISADKSSSTAYLQWSS LKASDTAMYFCARGGFYGSTIWFDFWGQGTMVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK (SEQ ID NO;

35, residues 20-455, inclusive);

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of A(i), above, provided that in any event the heavy chain comprises a first complementarity determining region (CDR) comprising a sequence of amino acid residues DHTIH (SEQ ID NO;

     13), a second CDR comprising a sequence of amino acid residues AISPRHDITKYNEMFRG (SEQ ID NO;

     31), and a third CDR comprising a sequence of amino acid residues GGFYGSTIWFDF (SEQ ID NO;

     15); and

B. each light chain comprises a sequence of amino acid residues having an amino acid sequence;

(i) ETTVTQSPSFLSASVGDRVTITCITTTDIDDDMNWFQQEPG KAPKLLISEGNILRPGVPSRFSSSGYGTDFTLTISKLQPEDFATYYCL QSDNLPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO;

37, residues 21-234, inclusive);

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of B(i), above, provided that in any event the light chain comprises a first CDR comprising a sequence of amino acid residues ITTTDIDDDMN (SEQ ID NO;

     10), a second CDR comprising a sequence of amino acid residues EGNILRP (SEQ ID NO;

     11), and a third CDR comprising a sequence of amino acid residues LQSDNLPFT (SEQ ID NO;

     12).

3. An isolated humanized antibody according to claim 2, wherein each heavy chain comprises a sequence of amino acid residues having an amino acid sequence EVQLVQSGAEVKKPG ESLKISCQSFGYIFIDHTIHWMRQMPGQGLEWMGAISPRHDITKYNEMFRGQVTISADKS SSTAYLQWSSLKASDTAMYFCARGGFYGSTIWFDFWGQGTMVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPG (SEQ ID NO:

38, residues 1-450, inclusive).

4. An isolated humanized antibody, according to claim 1 wherein at least one amino acid residue of the antibody is glycosylated.

5. A pharmaceutical composition comprising an isolated humanized antibody according to claim 1 and a pharmaceutically acceptable carrier.

6. An isolated humanized antibody that binds sphingosine-1-phosphate, wherein:

A. each heavy chain comprises;

i) an amino acid sequence that is the same as the amino acid sequence of the heavy chain encoded by the vector pATH1009 in ATCC Accession No. PTA-8421;

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of A(i), above, provided that in any event the heavy chain comprises a first complementarity determining region (CDR) comprising a sequence of amino acid residues DHTIH (SEQ ID NO;

     13), a second CDR comprising a sequence of amino acid residues AISPRHDITKYNEMFRG (SEQ ID NO;

     31), and a third CDR comprising a sequence of amino acid residues GGFYGSTIWFDF (SEQ ID NO;

     15); and

B. each light chain comprises;

(i) an amino acid sequence that is the same as the amino acid sequence of the light chain encoded by the vector pATH1009 in ATCC Accession No. PTA-8421;

or

(ii) a sequence of amino acid residues having at least about 80% sequence identity to the amino acid sequence of B(i), above, provided that in any event the light chain comprises a first CDR comprising a sequence of amino acid residues ITTTDIDDDMN (SEQ ID NO;

     10), a second CDR comprising a sequence of amino acid residues EGNILRP (SEQ ID NO;

     11), and a third CDR comprising a sequence of amino acid residues LQSDNLPFT (SEQ ID NO;

     12).

7. An isolated humanized antibody according to claim 6 wherein at least one amino acid residue of the antibody is glycosylated.

8. A pharmaceutical composition comprising an isolated humanized antibody according to claim 6 and a pharmaceutically acceptable carrier.