US2009214539A1PendingUtilityA1

B-cell reduction using cd37-specific and cd20-specific binding molecules

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Assignee: TRUBION PHARMACEUTICALS INCPriority: Jul 25, 2005Filed: May 7, 2009Published: Aug 27, 2009
Est. expiryJul 25, 2025(expired)· nominal 20-yr term from priority
Inventors:Laura Sue GrosmaireMartha Hayden-LedbetterJeffrey A. LedbetterPeter Armstrong ThompsonSandy Alexander SimonWilliam Brady
A61P 37/06A61P 37/00A61P 35/00A61P 43/00A61P 3/10A61P 37/02A61P 35/02A61P 29/00A61P 27/02A61P 25/00A61P 19/02A61P 1/04A61P 17/06A61P 21/04A61P 17/00A61P 21/00C07K 2317/567A61K 2039/505C07K 16/2896C07K 2317/53C07K 2317/76C07K 2317/52C07K 2317/72C07K 2317/734C07K 2317/565C07K 2317/622C07K 2317/75A61K 2039/545C07K 2317/73A61K 45/06C07K 2317/24C07K 2317/732C07K 16/2887A61K 2039/507A61K 39/3955A61K 39/39558C07K 16/30C07K 16/3061C07K 2317/56A61K 39/395
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Claims

Abstract

The present invention generally provides methods for B-cell reduction in an individual using CD37-specific binding molecules. In particular, the invention provides methods for B-cell reduction using CD37-specific binding molecules alone, or a combination of CD37-specific binding molecules and CD20-specific binding molecules, in some instances a synergistic combination. The invention further provides materials and methods for treatment of diseases involving aberrant B-cell activity. In addition, the invention provides humanized CD37-specific binding molecules.

Claims

exact text as granted — not AI-modified
1 . A humanized CD37-specific immunoglobulin binding molecule comprising:
 (a) human light chain framework regions, a light chain CDR1 comprising an amino acid sequence of SEQ ID NO:62 or a variant thereof in which one or two amino acids of SEQ ID NO:62 have been changed, a light chain CDR2 comprising an amino acid sequence of SEQ ID NO:64 or a variant thereof in which one or two amino acids of SEQ ID NO:64 have been changed, and a light chain CDR3 comprising an amino acid sequence of SEQ ID NO:66 or a variant thereof in which one or two amino acids of SEQ ID NO:66 have been changed; and   (b) human heavy chain framework regions, a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO:63 or a variant thereof in which one or two amino acids of SEQ ID NO:63 have been changed, a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO:65 or a variant thereof in which one or two amino acids of SEQ ID NO:65 have been changed, and a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO:69 or a variant thereof in which one or two amino acids of SEQ ID NO:69 have been changed;   wherein the humanized binding molecule competes with monoclonal antibody G28-1 for binding with human CD37.   
     
     
         2 . The humanized CD37-specific binding molecule of  claim 1  wherein the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:61 (RASENVYSYLA) or SEQ ID NO:62 (RTSENVYSYLA). 
     
     
         3 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:64 (FAKTLAE). 
     
     
         4 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:66 (QHHSDNPWT). 
     
     
         5 . The humanized CD37-specific binding molecule according to  claim 1  wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:63 (GYNMN). 
     
     
         6 . The humanized CD37-specific binding molecule according to  claim 1  wherein the heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:65 (NIDPYYGGTTYNRKFKG). 
     
     
         7 . The humanized CD37-specific binding molecule according to  claim 1  wherein the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:67 (SVGPFDY), SEQ ID NO:68 (SVGPFDS), or SEQ ID NO:69 (SVGPMDY). 
     
     
         8 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:61, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 67, respectively. 
     
     
         9 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:61, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 68, respectively. 
     
     
         10 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:61, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 69, respectively. 
     
     
         11 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:62, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 67, respectively. 
     
     
         12 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:62, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 68, respectively. 
     
     
         13 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:62, 64 and 66, respectively, and the heavy chain CDR1, CDR2 and CDR3 consist of the amino acid sequences of SEQ ID NOS:63, 65, and 69, respectively. 
     
     
         14 . The humanized CD37-specific binding molecule according to  claim 1  comprising a human light chain framework region selected from SEQ ID NOS:170-172, 175, 179-182, 184-188, 191, 194-198, 203 and 205-210. 
     
     
         15 . The humanized CD37-specific binding molecule according to  claim 1  comprising a human heavy chain framework region selected from SEQ ID NOS:140, 141, 143-147, 150, 151, 154-163, 168 and 169. 
     
     
         16 . The humanized CD37-specific binding molecule according to  claim 1  comprising a human light chain framework region selected from SEQ ID NOS: 170-172, 175, 179-182, 184-188, 191, 194-198, 203 and 205-210 and a human heavy chain framework region selected from SEQ ID NOS: 140, 141, 143-147, 150, 151, 154-163, 168 and 169. 
     
     
         17 . The humanized CD37-specific binding molecule according to  claim 1  comprising a first human light chain framework region (FR1) selected from SEQ ID NOS:170-172, 175 and 177-181, a human FR2 of the light chain framework region selected from SEQ ID NOS:182, 184-188 and 191, a human FR3 of the light chain selected from SEQ ID NOS:194-198, 203 and 205, and a human FR4 of the light chain selected from SEQ ID NOS:206-210. 
     
     
         18 . The humanized CD37-specific binding molecule according to  claim 1  comprising a first human heavy chain framework region (FR1) selected from SEQ ID NOS:140, 141 and 143-146, a human FR2 of the heavy chain selected from SEQ ID NOS:147, 150 and 151, a human FR3 of the heavy chain selected from SEQ ID NOS:154-160, and a human FR4 of the heavy chain selected from SEQ ID NOS:161-163, 168 and 169. 
     
     
         19 . The humanized CD37-specific binding molecule according to  claim 1  comprising:
 (a) a human FR1 of the light chain selected from SEQ ID NOS: 170-172, 175 and 177-181, a human FR2 of the light chain framework region selected from SEQ ID NOS: 182, 184-188 and 191, a human FR3 of the light chain selected from SEQ ID NOS: 194-198, 203 and 205, and a human FR4 of the light chain selected from SEQ ID NOS:206-210; and   (b) a human FR1 of the heavy chain selected from SEQ ID NOS: 140, 141 and 143-146, a human FR2 of the heavy chain selected from SEQ ID NOS: 147, 150 and 151, a human FR3 of the heavy chain selected from SEQ ID NOS:154-160, and a human FR4 of the heavy chain selected from SEQ ID NOS: 161-163, 168 and 169.   
     
     
         20 . The humanized CD37-specific binding molecule according to  claim 1  wherein the first human light chain framework region (FR1) comprises the amino acid sequence of SEQ ID NO:171; FR2 of the light chain comprises the amino acid sequence of SEQ ID NO:182; FR3 of the light chain comprises the amino acid sequence of SEQ ID NO:195; and FR4 of the light chain comprises the amino acid sequence of SEQ ID NO:206. 
     
     
         21 . The humanized CD37-specific binding molecule according to  claim 1  wherein the first human heavy chain framework region (FR1) comprises the amino acid sequence of SEQ ID NO:144; FR2 of the heavy chain comprises the amino acid sequence of SEQ ID NO:151; FR3 of the heavy chain comprises the amino acid sequence of SEQ ID NO:158; and FR4 of the heavy chain comprises the amino acid sequence of SEQ ID NO:161. 
     
     
         22 . The humanized CD37-specific binding molecule according to  claim 1  wherein the light chain framework regions and CDRs are comprised of a FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 that consist of the amino acid sequences of SEQ ID NOS:171, 61, 182, 64, 195, 66 and 206, respectively, and the heavy chain framework regions and CDRs are comprised of a FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 that consist of the amino acid sequences of SEQ ID NOS:144, 63, 151, 65, 158, 68 and 161, respectively. 
     
     
         23 . The humanized CD37-specific binding molecule according to  claim 1  wherein the binding molecule is a single chain Fv (scFv) polypeptide, an antibody or a binding fragment thereof, or a small modular immunopharmaceutical (SMIP) polypeptide. 
     
     
         24 . The humanized CD37-specific binding molecule according to  claim 23  wherein the binding molecule is chimeric or humanized. 
     
     
         25 . The humanized CD37-specific binding molecule according to  claim 1  wherein the binding molecule is a SMIP polypeptide comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region is attached to the heavy chain variable region by a linker peptide comprising (Gly 4 Ser) n , wherein n is 1, 2, 3, 4, 5, or 6. 
     
     
         26 . The humanized CD37-specific binding molecule according to  claim 25  wherein the linked light and heavy chain variable regions are connected to an effector domain via a hinge comprised of an amino acid sequence selected from the group consisting of SEQ ID NO:90, 92, 94, 96, 98, 100, 102, 104, 106, 108 110, 112, 115, 116, 118, 120, 122, 124, 126, or 127. 
     
     
         27 . The humanized CD37-specific binding molecule according to  claim 26  wherein the effector domain is an IgG1 domain. 
     
     
         28 . The humanized CD37-specific binding molecule of  claim 1  comprising an amino acid sequence selected from SEQ ID NO:6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 52, 80, 82, 84, 86, and 88. 
     
     
         29 . A composition comprising a humanized CD37-specific binding molecule according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . A method for treating disease associated with aberrant B-cell activity, comprising administering to a human subject in need thereof an effective amount of a humanized CD37-specific immunoglobulin binding molecule according to  claim 1 . 
     
     
         31 . The method according to  claim 30  wherein the binding molecule is a single chain Fv (scFv) polypeptide, an antibody or a binding fragment thereof, or a SMIP polypeptide. 
     
     
         32 . The method according to  claim 30  wherein the light chain framework regions and CDRs are comprised of a FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 that consist of the amino acid sequences of SEQ ID NOS:171, 61, 182, 64, 195, 66 and 206, respectively, and the heavy chain framework regions and CDRs are comprised of a FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 that consist of the amino acid sequences of SEQ ID NOS:144, 63, 151, 65, 158, 68 and 161, respectively. 
     
     
         33 . The method of  claim 30  wherein the binding molecule is a SMIP polypeptide selected from SEQ ID NO:6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 52, 80, 82, 84, 86, and 88. 
     
     
         34 . The method according to  claim 30  wherein the disease associated with aberrant B-cell activity is a B-cell cancer or an autoimmune disease. 
     
     
         35 . The method according to  claim 34  wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Chron's disease, Sjogren's syndrome, Grave's disease, type I diabetes mellitus, psoriasis, immune thrombocytopenic purpura, pemphigus, idiopathic inflammatory myopathy, or Waldenstrom's macroglobinemia. 
     
     
         36 . The method according to  claim 34  wherein the B-cell cancer is non-Hodgkin's lymphoma or chronic lymphocytic leukemia. 
     
     
         37 . The method according to  claim 30  wherein the binding molecule is administered in a dose range of about 0.01 mg/kg to about 50 mg/kg. 
     
     
         38 . The method according to  claim 30  wherein the binding molecule is administered in a dose range of about 5 mg/kg to about 15 mg/kg. 
     
     
         39 . The method according to  claim 30  wherein the binding molecule has an in circulation half-life of about 7 days to about 30 days.

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