|
|
Bristol-Myers Squibb Co.
|
 |
||||||||
|
 |
  |
 |
|
|
||
 |
 |
 
|
return to message board, top of board |
Building IP: BMY Patent Grant "Anti-CSF1R Antibody And Anti-PD-1 Antibody CombinationAnti-CSF1R Antibody And Anti-PD-1 Antibody Combination Therapy For Selected CancersDOCUMENT IDUS 11566076 B2 DATE PUBLISHED2023-01-31 INVENTOR INFORMATION NAMECITYSTATEZIP CODECOUNTRYWong; Brian Los Altos CA N/A US Hambleton; Julie San Francisco CA N/A US Sikorski; Robert Woodside CA N/A US Masteller; Emma Redwood City CA N/A US Hestir; Kevin Kensington CA N/A US Bellovin; David San Jose CA N/A US Lewis; Katherine E. Lake Forest Park WA N/A US APPLICANT INFORMATION NAME Five Prime Therapeutics, Inc. Bristol-Myers Squibb Company CITY South San Francisco Princeton STATE CA NJ ZIP CODE N/A N/A COUNTRY US US AUTHORITY N/A N/A TYPE assignee assignee ASSIGNEE INFORMATION NAME Five Prime Therapeutics, Inc. Bristol-Myers Squibb Company CITY Thousand Oaks Princeton STATE CA NJ ZIP CODE N/A N/A COUNTRY US US TYPE CODE 02 02 APPLICATION NO16/808910 DATE FILED2020-03-04 DOMESTIC PRIORITY (CONTINUITY DATA)continuation parent-doc US 14925534 20151028 US 9765147 20170909 child-doc US 15680664 division parent-doc US 16243510 20190109 US 10618967 child-doc US 16808910 division parent-doc US 15680664 20170818 US 10221244 20190305 child-doc US 16243510 us-provisional-application US 62192025 20150713 us-provisional-application US 62157368 20150505 us-provisional-application US 62072035 20141029 CPC CURRENT TYPECPCDATEAbstractMethods of treating cancer with antibodies that bind colony stimulating factor 1 receptor (CSF1R) in combination with PD-1/PD-L1 inhibitors are provided. Background/SummaryCROSS-REFERENCE TO RELATED APPLICATIONS (1) The present application is a divisional of U.S. application Ser. No. 16/243,510, filed Jan. 9, 2019, which is a divisional of U.S. application Ser. No. 15/680,664, filed Aug. 18, 2017, now U.S. Pat. No. 10,221,244, which is a continuation of U.S. application Ser. No. 14/925,534, filed Oct. 28, 2015, now U.S. Pat. No. 9,765,147, which claims the benefit of priority of US Provisional Application Nos. 62/072,035, filed Oct. 29, 2014, 62/157,368, filed May 5, 2015, and 62/192,025, filed Jul. 13, 2015, all of which are incorporated by reference herein in their entirety for any purpose. SEQUENCE LISTING (1) The present application is filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled “01134-0036-00US_SeqList_ST25.txt” created on Oct. 28, 2015, which is 167,217 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. TECHNICAL FIELD (2) Methods of treating cancer with antibodies that bind colony stimulating factor 1 receptor (CSF1R) in combination with PD-1/PD-L1 inhibitors. BACKGROUND (3) Colony stimulating factor 1 receptor (referred to herein as CSF1R; also referred to in the art as FMS, FIM2, C-FMS, M-CSF receptor, and CD115) is a single-pass transmembrane receptor with an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain with tyrosine kinase activity. Ligand binding of CSF1 or the interleukin 34 ligand (referred to herein as IL-34; Lin et al., Science 320: 807-11 (2008)) to CSF1R leads to receptor dimerization, upregulation of CSF1R protein tyrosine kinase activity, phosphorylation of CSF1R tyrosine residues, and downstream signaling events. CSF1R activation by CSF1 or IL-34 leads to the trafficking, survival, proliferation, and differentiation of monocytes and macrophages, as well as other monocytic cell lineages such as osteoclasts, dendritic cells, and microglia. (4) Many tumor cells or tumor stromal cells have been found to produce CSF1, which activates monocyte/macrophage cells through CSF1R. The level of CSF1 in tumors has been shown to correlate with the level of tumor-associated macrophages (TAMs) in the tumor. Higher levels of TAMs have been found to correlate with poorer patient prognoses in the majority of cancers. In addition, CSF1 has been found to promote tumor growth and progression to metastasis in, for example, human breast cancer xenografts in mice. See, e.g., Paulus et al., Cancer Res. 66: 4349-56 (2006). Further, CSF1R plays a role in osteolytic bone destruction in bone metastasis. See, e.g., Ohno et al., Mol. Cancer Ther. 5: 2634-43 (2006). TAMs promote tumor growth, in part, by suppressing anti-tumor T cell effector function through the release of immunosuppressive cytokines and the expression of T cell inhibitory surface proteins. (5) Genetic alterations in cancer provide a diverse set of antigens that can mediate anti-tumor immunity. Antigen recognition through T-cell receptors (TCRs) initiate T-cell-responses, which are regulated by a balance between activating and inhibitory signals. The inhibitory signals, or “immune checkpoints,” play an important role in normal tissues by preventing autoimmunity. Up-regulation of immune checkpoint proteins allows cancers to evade anti-tumor immunity. Two immune checkpoint proteins have been the focus of clinical cancer immunotherapeutics, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody has been approved for the treatment of metastatic melanoma and several additional clinical trials are also ongoing to study the use of this combination for the treatment of other cancers. Anti-PD-1 antibodies and anti-CTLA-4 antibodies for use as monotherapies are also currently being studied in clinical trials as a treatment for many different types of cancer. Anti-PD-L1 antibodies which bind PD-L1, one of the ligands for PD-1, are also currently in clinical development. (6) Many tumors often express multiple checkpoint molecules simultaneously, Therefore, combinations of checkpoint modulators are undergoing clinical testing with aim of improved efficacy. Initial clinical results of the combination of an anti-CTLA-4 antibody (anti-CTLA-4 Ab) and an anti-PD-1 antibody (anti-PD-1 Ab) have demonstrated improved overall response rates, increased complete response rates, as well as overall survival rates in metastatic melanoma, compared to anti-CTLA-4 Ab alone or historical controls. (7) As described herein, significant antitumor activity of an anti-PD-1 antibody in combination with an anti-CSF1R antibody has been demonstrated in clinical trials. SUMMARY (8) In some embodiments, methods of treating cancer in a subject are provided, comprising administering to the subject an anti-CSF1R antibody and a PD-1/PD-L1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor is an antibody. In some embodiments, the PD-1/PD-L1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody comprises the heavy chain and light chain CDRs of an antibody selected from nivolumab and pembrolizumab. In some embodiments, the anti-PD-1 antibody comprises the heavy chain and light chain variable regions of an antibody selected from nivolumab and pembrolizumab. In some embodiments, the anti-PD-1 antibody is selected from nivolumab and pembrolizumab. In some embodiments, the PD-1/PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises the heavy chain and light chain CDRs of an antibody selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the anti-PD-L1 antibody comprises the heavy chain and light chain variable regions of an antibody selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the anti-PD-L1 antibody is selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the PD-1/PD-L1 inhibitor is a fusion protein. In some embodiments, the fusion protein is AMP-224. (9) In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered concurrently or sequentially. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered concurrently. In some embodiments, one or more doses of the PD-1/PD-L1 inhibitor are administered prior to administering an anti-CSF1R antibody. In some embodiments, the subject received a complete course of PD-1/PD-L1 inhibitor therapy prior to administration of the anti-CSF1R antibody. In some embodiments, the anti-CSF1R antibody is administered during a second course of PD-1/PD-L1 inhibitor therapy. In some embodiments, the subject received at least one, at least two, at least three, or at least four doses of the PD-1/PD-L1 inhibitor prior to administration of the anti-CSF1R antibody. In some embodiments, at least one dose of the PD-1/PD-L1 inhibitor is administered concurrently with the anti-CSF1R inhibitor. In some embodiments, one or more doses of the anti-CSF1R antibody are administered prior to administering a PD-1/PD-L1 inhibitor. In some embodiments, the subject received at least two, at least three, at least three, or at least four doses of the anti-CSF1R antibody prior to administration of the PD-1/PD-L1 inhibitor. In some embodiments, at least one dose of the anti-CSF1R antibody is administered concurrently with the PD-1/PD-L1 inhibitor. In some embodiments, the two drugs are administered on the same day. In some embodiments, the drugs are mixed together prior to administration and thus administered as a mixtre. For example, in some embodiments, the drugs may be packaged and stored in the same vial (i.e., fixed dose formulation), or alternatively, vials containing each separate drug may be mixed together just prior to administration. In various embodiments, the drugs may be administered in vivo by various routes, including, but not limited to, oral, intra-arterial, parenteral, intranasal, intravenous, intramuscular, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation. (10) In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, about once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. (11) In certain embodiments, the first dose is a therapeutic dose and the second dose is a therapeutic dose. In other embodiments, the first dose is a subtherapeutic dose and the second dose is a therapeutic dose. In some embodiments, the first dose is administered at a dose ranging from at least about 80 mg to at least about 800 mg or at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight. In some embodiments, the second dose is administered at a dose ranging from at least about 80 mg to at least about 800 mg or at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight. In one particular embodiment, the first dose is administered at a dose of at least about 3 mg/kg body weight or 240 mg once about every 2 weeks. (12) In some embodiments, the subject is administered at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least 12 doses, at least 20 doses. (13) In some embodiments, the first dose is a flat dose or a weight based dose. In other embodiments, the second dose is a flat dose or a weight based dose. (14) In some embodiments, the cancer is selected from non-small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, ovarian cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and endometrial cancer. In some embodiments, the cancer is a central nervous system neoplasm. In some embodiments, the central nervous system neoplasm is a malignant glioma or glioblastoma. In some embodiments, the cancer is recurrent or progressive after a therapy selected from surgery, chemotherapy, radiation therapy, or a combination thereof. In some embodiments, the patient has stage III or stage IV cancer, as defined in the definitions section below with respect to particular cancers. In some embodiments, the patient's cancer is metastatic. In some embodiments, the subject is a PD-1/PD-L1 inhibitor inadequate responder or is refractory to prior treatment with a PD-1/PD-L1 inhibitor. In some embodiments, the subject has previously received PD-1/PD-L1 inhibitor therapy, and in other embodiments the subject has not previously received PD-1/PD-L1 inhibitor therapy. In some embodiments, the patient has previously received one or more of chemotherapy, radiation therapy, or surgery; in some such embodiments the patient has documented tumor progression in spite of such prior treatment. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for the cancer compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (15) In some embodiments of the methods a patient with non-small cell lung cancer (NSCLC) is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some such embodiments, the patient has Stage IIIB or IV disease and/or has demonstrated disease progression or recurrence during and/or after a platinum doublet-based or other chemotherapy regimen for advanced or metastatic disease. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for NSCLC compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (16) In some embodiments of the methods, melanoma is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some such embodiments, the patient has Stage III or IV melanoma. In some embodiments, the patient has demonstrated disease progression during or after treatment with at least one BRAF inhibitor, or is BRAF wild-type. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for melanoma compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (17) In some embodiments of the methods, squamous cell carcinoma of the head and neck (SSCHN) is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some embodiments, the patient has Stage III or IV SSCHN or has recurrent or metastatic SSCHN. In some embodiments, the patient has previously received chemotherapy, such as platinum therapy, but has demonstrated tumor progression or recurrence. In some embodiments, the patient has previously received radiation therapy, optionally along with platinum therapy, but has demonstrated tumor progression or recurrence. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for squamous cell carcinoma compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (18) In some embodiments of the methods, pancreatic cancer is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some embodiments, the patient has documented localized or metastatic adenocarcinoma of the pancreas. In some embodiments, the patient may previously have received surgery and/or radiation therapy. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of 0.1, 0.3, 1, 2, 3, or 4 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.5-10 mg/kg, such as, for example 1, 2, 3, 4, or 5 mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as once every 2 weeks. In some embodiments of the methods, colorectal cancer is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some embodiments, the patient has adenocarcinoma of the colon or rectum. In some embodiments, the patient has metastatic colorectal cancer. In some embodiments, the patient has metastatic colorectal cancer despite prior treatment with one or more of fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab, or panitumumab. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for pancreatic cancer (such as a model comprising KRas.sup.G12D/Ink4a.sup.−/− murine pancreatic ductal adenocarcinoma (PDAC) cells) compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (19) In some embodiments of the methods, malignant glioma (e.g. glioblastoma or gliosarcoma) is treated with the anti-CSF1R antibody (for instance, an anti-CSF1R antibody as described herein, such as an antibody comprising the heavy and light chain CDRs of HuAB1) and the PD-1/PD-L1 inhibitor (for instance, an anti-PD-1 antibody comprising the heavy chain and light chain CDRs of nivolumab or pembrolizumab or a PD-1/PD-L1 inhibitor fusion protein or peptide such as AMP-224 or AUR-012). In some embodiments, the patient has previously been treated with surgery, radiotherapy, and/or temozolomide. In some embodiments, the patient has Grade IV malignant glioma. In some embodiments, the patient has not had prior exposure to a PD-1/PD-L1 inhibitor, and in other embodiments, the patient is refractory to PD-1/PD-L1 inhibitor treatment. In some embodiments, the anti-CSF1R antibody is administered at a dose of about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg. In some embodiments, the PD-1/PD-L1 inhibitor is administered at a dose of 0.1-10 mg/kg, such as, for example about 0.1, about 0.3, about 0.5, about 1, about 2, about 3, about 4, about 5 or about 10 mg/kg mg/kg. In some embodiments, the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor are administered, for example at one of the above doses, once per 1, 2, 3, 4, or 5 weeks, such as about once every 2 weeks. In some embodiments, administration of the anti-CSF1R antibody and the PD-1/PD-L1 inhibitor results in a synergistic effect on tumor growth, weight, and/or volume compared in a mouse xenograft model for glioma compared to administration of the anti-CSF1R antibody or PD-1/PD-L1 inhibitor alone. (20) In some embodiments, the method further comprises administering one or more additional anti-cancer agents. In certain embodiments, the anti-cancer agent is selected from the group consisting of an antibody or antigen-binding portion thereof that binds specifically to CTLA-4 (“anti-CTLA-4 antibody or antigen-binding portion thereof”) and inhibits CTLA-4 activity, a chemotherapy, a platinum-based doublet chemotherapy, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, an Indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor, or any combination thereof. In one embodiment, the anti-cancer agent is ipilimumab. (21) In some embodiments, compositions are provided, comprising an anti-CSF1R antibody and a PD-1/PD-L1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor is an antibody. In some embodiments, the PD-1/PD-L1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody comprises the heavy chain and light chain CDRs of an antibody selected from nivolumab and pembrolizumab. In some embodiments, the anti-PD-1 antibody comprises the heavy chain and light chain variable regions of an antibody selected from nivolumab and pembrolizumab. In some embodiments, the anti-PD-1 antibody is selected from nivolumab and pembrolizumab. In some embodiments, the PD-1/PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises the heavy chain and light chain CDRs of an antibody selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the anti-PD-1 antibody comprises the heavy chain and light chain variable regions of an antibody selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the anti-PD-1 antibody is selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. In some embodiments, the PD-1/PD-L1 inhibitor is a fusion protein. In some embodiments, the fusion protein is AMP-224. (22) In any of the compositions or methods described herein, the antibody heavy chain and/or the antibody light chain of the anti-CSF1R antibody may have the structure described below. (23) In any of the compositions or methods described herein, the anti-CSF1R antibody heavy chain may comprise a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45. In any of the methods described herein, the anti-CSF1R antibody light chain may comprise a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 10, 12, 14, and 46 to 52. In any of the compositions or methods described herein, the anti-CSF1R antibody heavy chain may comprise a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 9, 11, 13, and 39 to 45, and the anti-CSF1R antibody light chain may comprise a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 10, 12, 14, and 46 to 52. (24) In any of the compositions or methods described herein, the anti-CSF1R antibody HC CDR1, HC CDR2, and HC CDR3 may comprise a set of sequences selected from: (a) SEQ ID NOs: 15, 16, and 17; (b) SEQ ID NOs: 21, 22, and 23; and (c) SEQ ID NOs: 27, 28, and 29. In any of the compositions or methods described herein, the anti-CSF1R antibody LC CDR1, LC CDR2, and LC CDR3 may comprise a set of sequences selected from: (a) SEQ ID NOs: 18, 19, and 20; (b) SEQ ID NOs: 24, 25, and 26; and (c) SEQ ID NOs: 30, 31, and 32. (25) In any of the compositions or methods described herein, the anti-CSF1R antibody heavy chain may comprise an HC CDR1, HC CDR2, and HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 comprise a set of sequences selected from: (a) SEQ ID NOs: 15, 16, and 17; (b) SEQ ID NOs: 21, 22, and 23; and (c) SEQ ID NOs: 27, 28, and 29; and the light chain may comprise an LC CDR1, LC CDR2, and LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 comprise a set of sequences selected from: (a) SEQ ID NOs: 18, 19, and 20; (b) SEQ ID NOs: 24, 25, and 26; and (c) SEQ ID NOs: 30, 31, and 32. (26) In any of the compositions or methods described herein, the anti-CSF1R antibody may comprise: (a) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 9 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 10; (b) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 11 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 12; (c) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 13 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 14; (d) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 39 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 46; (e) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 40 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 46; (f) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 41 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 46; (g) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 39 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 47; (h) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 40 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 47; (i) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 41 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 47; and (j) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 42 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 48; (k) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 42 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 49; (1) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 42 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 50; (m) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 43 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 48; (n) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 43 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 49; (o) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 43 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 50; (p) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 44 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 51; (q) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 44 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 52; (r) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 45 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 51; or (s) a heavy chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 45 and a light chain comprising a sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 52. (27) In any of the compositions or methods described herein, the anti-CSF1R antibody may comprise: (a) a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 15, an HC CDR2 having the sequence of SEQ ID NO: 16, and an HC CDR3 having the sequence of SEQ ID NO: 17, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 18, a LC CDR2 having the sequence of SEQ ID NO: 19, and a LC CDR3 having the sequence of SEQ ID NO: 20; (b) a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 21, an HC CDR2 having the sequence of SEQ ID NO: 22, and an HC CDR3 having the sequence of SEQ ID NO: 23, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 24, a LC CDR2 having the sequence of SEQ ID NO: 25, and a LC CDR3 having the sequence of SEQ ID NO: 26; or (c) a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 27, an HC CDR2 having the sequence of SEQ ID NO: 28, and an HC CDR3 having the sequence of SEQ ID NO: 29, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 30, a LC CDR2 having the sequence of SEQ ID NO: 31, and a LC CDR3 having the sequence of SEQ ID NO: 32. (28) In any of the compositions or methods described herein, the anti-CSF1R antibody may comprise: (a) a heavy chain comprising a sequence of SEQ ID NO: 53 and a light chain comprising a sequence of SEQ ID NO: 60; (b) a heavy chain comprising a sequence of SEQ ID NO: 53 and a light chain comprising a sequence of SEQ ID NO: 61; or (c) a heavy chain comprising a sequence of SEQ ID NO: 58 and a light chain comprising a sequence of SEQ ID NO: 65. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the antibody comprises: (a) a heavy chain consisting of the sequence of SEQ ID NO: 53 and a light chain consisting of the sequence of SEQ ID NO: 60; (b) a heavy chain consisting of the sequence of SEQ ID NO: 53 and a light chain consisting of the sequence of SEQ ID NO: 61; or (c) a heavy chain consisting of the sequence of SEQ ID NO: 58 and a light chain consisting of the sequence of SEQ ID NO: 65. (29) In any of the compositions or methods described herein, the anti-CSF1R antibody may bind to human CSF1R and/or binds to cynomolgus CSF1R. In any of the compositions or methods described herein, the anti-CSF1R antibody may block ligand binding to CSF1R. In any of the compositions or methods described herein, the anti-CSF1R antibody may block binding of CSF1 and/or IL-34 to CSF1R. In any of the compositions or methods described herein, the anti-CSF1R antibody may block binding of both CSF1 and IL-34 to CSF1R. In any of the compositions or methods described herein, the anti-CSF1R antibody may inhibit ligand-induced CSF1R phosphorylation. In any of the compositions or methods described herein, the anti-CSF1R antibody may inhibit CSF1- and/or IL-34-induced CSF1R phosphorylation. In any of the compositions or methods described herein, the anti-CSF1R antibody may bind to human CSF1R with an affinity (K.sub.D) of less than 1 nM. In any of the compositions or methods described herein, the anti-CSF1R antibody may inhibit monocyte proliferation and/or survival responses in the presence of CSF1 or IL-34. (30) In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody, such as an anti-PD-1 antibody, with a structure described below. (31) In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody with an antibody heavy chain may comprising a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 100 and 101. In any of the methods described herein, the PD-1/PD-L1 inhibitor may be an antibody with an antibody light chain comprising a sequence that is at least 90%, at least 95%, at least 97%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 102 and 103. (32) In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody with heavy chain (HC) CDR1, HC CDR2, and HC CDR3 comprising a set of sequences selected from SEQ ID NOs: 105, 107, and 109. In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody with light chain (LC) CDR1, LC CDR2, and LC CDR3 may comprise a set of sequences selected from SEQ ID NOs: 112, 114, and 116. (33) In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody comprising: (a) a heavy chain comprising a variable region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 100 and a light chain comprising a variable region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 102; (b) a heavy chain comprising a constant region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 101 and a light chain comprising a constant region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 103; (c) a heavy chain comprising a variable region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 100 and a light chain comprising a variable region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 102; and/or (d) a heavy chain comprising a constant region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 101 and a light chain comprising a constant region sequence that is at least 95%, at least 97%, at least 99%, or 100% identical to SEQ ID NO: 103. (34) In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody comprising: a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 105, an HC CDR2 having the sequence of SEQ ID NO: 107, and an HC CDR3 having the sequence of SEQ ID NO: 109, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 112, a LC CDR2 having the sequence of SEQ ID NO: 114, and a LC CDR3 having the sequence of SEQ ID NO: 116. In any of the compositions or methods described herein, the PD-1/PD-L1 inhibitor may be an antibody comprising: a heavy chain comprising a heavy chain (HC) FR1 having the sequence of SEQ ID NO: 104, an HC FR2 having the sequence of SEQ ID NO: 106, an HC FR3 having the sequence of SEQ ID NO: 108, and an HC FR4 having the sequence of SEQ ID NO: 110; and/or, a light chain comprising a light chain (LC) FR1 having the sequence of SEQ ID NO: 111, a LC FR2 having the sequence of SEQ ID NO: 113, a LC FR3 having the sequence of SEQ ID NO: 115, and a LC FR4 having the sequence of SEQ ID NO: 117. (35) In any of the compositions or methods described herein, the anti-CSF1R antibody or PD-1/PD-L1 inhibitor may be a humanized or chimeric antibody. In any of the compositions or methods described herein, the anti-CSF1R or PD-1/PD-L1 inhibitor may be selected from a Fab, an Fv, an scFv, a Fab′, and a (Fab′).sub.2. In any of the compositions or methods described herein, the anti-CSF1R or PD-1/PD-L1 inhibitor may be selected from an IgA, an IgG, and an IgD. In any of the compositions or methods described herein, the anti-CSF1R antibody or PD-1/PD-L1 inhibitor may be an IgG. In any of the methods described herein, the antibody may be an IgG1, IgG2 or IgG4. (36) In any of the methods described herein, the tumor may or may not express PD-L1. In some embodiments, the tumor is PD-L1 positive. In other embodiments, the tumor is PD-L1 negative. In any of the methods described herein, the tumor may or may not express PD-L2. In some embodiments, the tumor is PD-L2 positive. In other embodiments, the tumor is PD-L2 negative. |
|
|
return to message board, top of board |
