US2014363453A1PendingUtilityA1

Methods for Increasing Efficacy of FOLR1 Cancer Therapy

61
Assignee: IMMUNOGEN INCPriority: Apr 1, 2011Filed: Apr 4, 2014Published: Dec 11, 2014
Est. expiryApr 1, 2031(~4.7 yrs left)· nominal 20-yr term from priority
Inventors:Christina N. CarriganKathleen R. WhitemanGillian PayneSharron Ladd
A61P 35/00A61P 43/00G01N 33/5759A61K 47/6869C07K 16/28A61K 47/6809A61K 47/6849A61K 47/6851A61K 47/48638G01N 2800/52A61K 2039/505G01N 33/577A61K 39/395A61K 47/6817A61K 47/6857
61
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Claims

Abstract

Methods to improve the success of cancer therapies that target the human folate receptor 1 are provided. Kits comprising reagent useful in the methods are further provided.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for increasing the efficacy of cancer therapy comprising administering a therapeutically effective dose of an anti-Folate Receptor 1 (FOLR1) immunoconjugate to a subject having cancer;
 wherein a tumor sample from the subject exhibits increased expression of FOLR1 using a detection method that distinguishes between staining intensity or staining uniformity in a FOLR1 expressing cancer sample as compared to staining intensity or staining uniformity in one or more reference samples; and   wherein the anti-FOLR1 immunoconjugate has the formula (A)-(L)-(C), wherein:   (A) comprises an antibody or antigen binding fragment thereof comprising the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5,   (L) comprises the linker N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB), and   (C) comprises the cytotoxic agent N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), and   wherein the linker (L) links (A) to (C).   
     
     
         2 . The method of  claim 1 , wherein the antibody or antigen binding fragment thereof of the anti-FOLR1 immunoconjugate comprises the light chain variable domain of SEQ ID NO: 5. 
     
     
         3 . The method of  claim 1 , further comprising detecting FOLR1 expression in the tumor sample from the subject using the detection method prior to administering the therapeutically effective dose of the anti-FOLR1 immunoconjugate to the subject having cancer. 
     
     
         4 . The method of  claim 3 , wherein the detection method produces a range of staining intensity for samples having weak FOLR1 expression, moderate FOLR1 expression, or strong FOLR1 expression. 
     
     
         5 . The method of  claim 3 , wherein the detection method is immunohistochemistry (IHC). 
     
     
         6 . The method of  claim 5 , wherein the IHC can distinguish between different levels of FOLR1 staining intensity. 
     
     
         7 . The method of  claim 6 , wherein the cancer sample is a formalin fixed paraffin embedded sample. 
     
     
         8 . The method of  claim 6 , wherein the cancer sample has an IHC staining intensity score of 2 or greater for FOLR expression. 
     
     
         9 . The method of  claim 8 , wherein the cancer sample has an IHC staining uniformity for FOLR1 expression that is heterogeneous or homogeneous. 
     
     
         10 . The method of  claim 9 , wherein the cancer sample has an IHC staining uniformity for FOLR1 expression that is homogeneous. 
     
     
         11 . The method of  claim 9 , wherein the subject has non-small cell lung cancer (NSCLC) or endometrial cancer. 
     
     
         12 . The method of  claim 9 , wherein the subject has ovarian cancer. 
     
     
         13 . The method of  claim 9 , wherein the cancer sample has an IHC staining intensity score of 3 or greater for FOLR1 expression. 
     
     
         14 . The method of  claim 13 , wherein the subject has non-small cell lung cancer (NSCLC) or endometrial cancer. 
     
     
         15 . The method of  claim 13 , wherein the subject has ovarian cancer. 
     
     
         16 . The method of  claim 3 , wherein the reference sample is a negative reference sample. 
     
     
         17 . The method of  claim 3 , wherein the reference sample comprises cells, cell pellets, or tissue. 
     
     
         18 . The method of  claim 3 , wherein the detection method comprises detecting FOLR1 expression with an antibody or antigen binding fragment thereof that specifically binds FOLR1. 
     
     
         19 . The method of  claim 18 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression comprises the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5. 
     
     
         20 . The method of  claim 18 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody huMov19. 
     
     
         21 . The method of  claim 18 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody BN3.2. 
     
     
         22 . The method of  claim 18 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression further comprises a detection reagent selected from the group consisting of: an enzyme, a fluorophore, a radioactive label, and a luminophore. 
     
     
         23 . The method of  claim 22 , wherein the detection reagent is selected from the group consisting of: biotin, digoxigenin, fluorescein, tritium, and rhodamine. 
     
     
         24 . A method for increasing the efficacy of cancer therapy comprising:
 (a) measuring the level of FOLR1 expression in a tumor tissue sample obtained from a tumor of a subject having cancer using a detection method;   (b) determining a FOLR1 staining intensity score for the tumor tissue sample;   (c) comparing the FOLR1 staining intensity score determined in step (b) to a reference value, wherein a FOLR1 staining intensity score for the sample determined in step (b) that is equal to or higher than the reference value identifies the tumor as being sensitive to treatment with an anti-FOLR1 immunoconjugate; and   (d) administering an anti-FOLR1 immunoconjugate to the subject when the FOLR1 staining intensity score for the tumor tissue sample determined in step (b) is equal to or higher than the reference value;   wherein the anti-FOLR1 immunoconjugate has the formula (A)-(L)-(C), wherein:   (A) comprises an antibody or antigen binding fragment thereof comprising the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5,   (L) comprises the linker N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB), and   (C) comprises the cytotoxic agent N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), and   wherein the linker (L) links (A) to (C).   
     
     
         25 . The method of  claim 24 , wherein the detection method comprises detecting FOLR1 expression with an antibody or antigen binding fragment thereof that specifically binds FOLR1. 
     
     
         26 . The method of  claim 25 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression comprises the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5. 
     
     
         27 . The method of  claim 25 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody huMov19. 
     
     
         28 . The method of  claim 25 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody BN3.2. 
     
     
         29 . The method of  claim 24 , wherein the reference value is determined by measuring FOLR1 protein expression in at least one reference sample. 
     
     
         30 . The method of  claim 29 , wherein the reference sample comprises tissue, cells, or cell pellets. 
     
     
         31 . The method of  claim 29 , wherein the reference sample is a negative reference sample. 
     
     
         32 . The method of  claim 24 , wherein the subject has a cancer selected from the group consisting of: non-small cell lung cancer (NSCLC), endometrial cancer, and ovarian cancer. 
     
     
         33 . A method for increasing the efficacy of cancer therapy comprising:
 (a) contacting a tumor tissue sample from a subject having cancer with an antibody or antigen binding fragment thereof that specifically binds FOLR1, wherein the sample is formalin-fixed paraffin embedded;   (b) measuring the binding of the antibody or antigen binding fragment thereof to FOLR1 in the tumor tissue sample in step (a) using a detection method that can distinguish between staining intensity or staining uniformity in a FOLR1 expressing cancer sample as compared to staining intensity or staining uniformity in one or more reference samples;   (c) assigning a FOLR1 expression score to the tumor tissue sample after comparing the level of FOLR1 staining intensity or staining uniformity in the tumor tissue sample to one or more reference samples; and   (d) administering an anti-FOLR1 immunoconjugate to the subject when the FOLR1 expression score for the tumor tissue sample assigned in step (c) is greater than 1;   wherein the anti-FOLR1 immunoconjugate has the formula (A)-(L)-(C), wherein:   (A) comprises an antibody or antigen binding fragment thereof comprising the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5,   (L) comprises the linker N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB), and   (C) comprises the cytotoxic agent N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), and   wherein the linker (L) links (A) to (C).   
     
     
         34 . The method of  claim 33 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression comprises the heavy chain variable domain of SEQ ID NO: 3 and the light chain variable domain of SEQ ID NO: 4 or 5. 
     
     
         35 . The method of  claim 33 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody huMov19. 
     
     
         36 . The method of  claim 33 , wherein the antibody or antigen binding fragment thereof for detecting FOLR1 expression is the antibody BN3.2. 
     
     
         37 . The method of  claim 33 , wherein the reference sample comprises tissue, cells, or cell pellets. 
     
     
         38 . The method of  claim 33 , wherein the reference sample is a negative reference sample. 
     
     
         39 . The method of  claim 33 , wherein the tumor tissue sample has a staining uniformity for FOLR1 expression that is heterogeneous or homogeneous. 
     
     
         40 . The method of  claim 39 , wherein the tumor tissue sample has a staining uniformity for FOLR1 expression that is homogeneous. 
     
     
         41 . The method of  claim 39 , wherein the subject has non-small cell lung cancer (NSCLC) or endometrial cancer. 
     
     
         42 . The method of  claim 39 , wherein the subject has ovarian cancer. 
     
     
         43 . The method of  claim 39 , wherein the tumor tissue sample has an FOLR1 expression score of 3 or greater. 
     
     
         44 . The method of  claim 43 , wherein the subject has non-small cell lung cancer (NSCLC) or endometrial cancer. 
     
     
         45 . The method of  claim 43 , wherein the subject has ovarian cancer.

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