Methods of treating pancreatic tumors expressing certain biomarkers

Abstract

Provided herein are methods of treating a subject having cancer, such as pancreatic cancer.

Description

Atty. Dkt. No. 144265-0107METHODS OF TREATING PANCREATIC TUMORS EXPRESSING CERTAIN BIOMARKERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit and priority to US Provisional Application 63 / 683,119, filed August 14, 2024, the disclosure of which is incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. The .XML file was created on August 5, 2025 and is named 144265-0107_SL.xml and is 72,289 bytes in size. The sequence listing contained in this .XML is part of the specification and is hereby incorporated by reference in its entirety. Sequences may also be found in Table S below.FIELD

[0003] Provided herein are methods of treating a subject having cancer, such as pancreatic cancer.BACKGROUND

[0004] Pancreatic cancer is the eighth most frequently diagnosed cancer and the fourth leading cause of cancer-related death worldwide. In the United States, approximately 75,000 new cases of pancreatic cancer will be diagnosed in 2024 and there will be approximately 50,000 pancreatic cancer related deaths. Pancreatic cancer remains difficult to cure because most patients present with advanced disease. The prognosis for pancreatic cancer is poor, with a 5-year overall survival (OS) rate estimated around 11%. Determining effective treatments strategies that provide increased response rates and clinical outcomes in treatments for pancreatic cancer can help increase the prognosis of pancreatic cancer.

[0005] While impressive and durable responses are observed in subsets of cancer patients treated with anti-PD-1 agents, various clinical studies have demonstrated that anti-PD- 1 agents as a monotherapy or in combination with additional immuno-oncology therapies (i.e., CTLA-4 agents) or chemotherapy have minimal effects in pancreatic cancer patients. For example, see Callahan, Margaret, et al., J. Immunother. Cancer 12.2 (2024): e007883;14930-8149-5134.1Atty. Dkt. No. 144265-0107O’Reilly, Eileen M., et al., JAMA Oncol. 5.10 (2019): 1431-1438; Brahmer, Julie R., et al., N. Engl. J. Med. 366.26 (2012): 2455-2465; Royal, Richard E., et al., J. Immunother. 33.8 (2010): 828-833; Wainberg, Zev A., et al., Clin. Cancer Res. 26.18 (2020): 4814-4822; Cheng, Ke, et al., Signal Transduct. Target. Ther. 9.1 (2024): 321; Padron, Lacey J., et al., Nat. Med. 28.6 (2022): 1167-1177; Renouf, Daniel J., et al., Nat. Commun. 13.1 (2022): 5020; Morizane, Chigusa, et al., BJC Rep. 2.1 (2024): 3; and Fu, Qihan, et al., Ann. Surg. Oncol. 30.8 (2023): 5071-5080.

[0006] Biomarkers are genes, proteins, and other substances in the body that can provide information about a person’s cancer. Biomarkers can be used to determine the type of cancer, the expected outlook (prognostic value), and / or the likelihood that a patient will respond to a given treatment (predictive value).

[0007] Some types of cancer treatments, including targeted therapies and immunotherapies, may only work for people whose cancers have certain biomarkers, while some treatments have increased response rates in patients with certain biomarkers. Determining a level of biomarkers in certain types of cancers can be important for selecting treatments that patients are most likely to respond to, while also helping patients avoid treatments with negative side effects that are unlikely to help. This is especially important in cancers that present in the advanced states and cancers that have low response rates.

[0008] What is needed are better methods of treating pancreatic cancer.SUMMARY

[0009] Provided herein are methods of treating pancreatic cancer by administering combination therapies with a CD39 antibody, a chemotherapy comprising one or more of gemcitabine and nab-paclitaxel, and optionally a PD-1 or anti-PD-Ll antibody. Further provided herein are treatments based on certain biomarkers or a combination of biomarkers.

[0010] A first aspect provides a method of treating a pancreatic cancer, the method comprising administering a therapeutically effective amount of an anti-CD39 antibody in combination with a chemotherapy to a human subject having a pancreatic cancer. In some embodiments, the anti-CD39 antibody consists of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76.24930-8149-5134.1Atty. Dkt. No. 144265-0107

[0011] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, the anti-CD39 antibody is administered in combination with the chemotherapy.

[0012] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles.

[0013] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.

[0014] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0015] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).

[0016] A second aspect provides a method of treating a pancreatic cancer, the method comprising administering a therapeutically effective amount of an anti-CD39 antibody in combination with a chemotherapy, and a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-Ll antibody, to a human subject having a pancreatic cancer. In some embodiments, the anti-CD39 antibody consists of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76.34930-8149-5134.1Atty. Dkt. No. 144265-0107

[0017] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, the anti-CD39 antibody is administered in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD-Ll antibody.

[0018] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles. In some embodiments, the anti- PD-1 antibody (e.g., budigalimab) is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.

[0019] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.

[0020] In some embodiments, the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78, and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

[0021] In some embodiments, the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

[0022] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS), and progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of44930-8149-5134.1Atty. Dkt. No. 144265-0107 care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0023] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).

[0024] A third aspect provides a method of treating a pancreatic cancer, the method comprising administering a therapeutically effective amount of an anti-CD39 antibody in combination with a chemotherapy, and optionally a therapeutically effective amount of an anti- PD-1 antibody or anti-PD-Ll antibody, to a human subject having a pancreatic cancer, the anti- CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76, wherein the patient is characterized as having HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA- DQB 1 *06 DNA sequences in the genome.

[0025] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, the anti-CD39 antibody is administered in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD-Ll antibody. In some embodiments, the qualified or validated assay detecting the presence or absence of HLA- DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 in the genome comprises or consists of Sanger Sequencing or Next Generation Sequencing.

[0026] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles. In some embodiments, the anti- PD-1 antibody (e.g., budigalimab) is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.

[0027] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment54930-8149-5134.1Atty. Dkt. No. 144265-0107 cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.

[0028] In some embodiments, the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78, and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

[0029] In some embodiments, the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

[0030] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0031] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).64930-8149-5134.1Atty. Dkt. No. 144265-0107

[0032] A fourth aspect provides a method of treating a pancreatic cancer that expressesHLA-DQA1 or HLA-DQB1, the method comprising administering a therapeutically effective amount of an anti-CD39 antibody in combination with a chemotherapy, and optionally a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-Ll antibody, to a human subject having a pancreatic cancer, the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76, wherein the cancer is characterized as having a high level of HLA-DQA1 and / or HLA-DQB1 when assessed by a qualified or validated assay measuring mRNA expression levels.

[0033] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, anti-CD39 antibody is administered in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD-Ll antibody. In some embodiments, the qualified or validated assay measuring mRNA expression levels comprises or consists of RT-PCR. In some embodiments, the qualified or validated assay measuring mRNA expression levels comprises or consists of RT-qPCR or multiplex nucleic acid hybridization technology, such as Nanostring.

[0034] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles. In some embodiments, the anti-PD-1 antibody (e.g., budigalimab) is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.

[0035] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.

[0036] In some embodiments, the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or74930-8149-5134.1Atty. Dkt. No. 144265-0107(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

[0037] In some embodiments, the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

[0038] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0039] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).

[0040] A fifth aspect provides a method of treating a pancreatic cancer that expresses HLA-DQA1 and / or HLA-DQB1 in a plurality of human subjects, the method comprising or consisting of administering a therapeutically effective amount of an anti-CD39 antibody in combination with chemotherapy, and optionally a therapeutically effective amount of an anti- PD-1 antibody or anti-PD-Ll antibody, to a human subject having the pancreatic cancer, the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of84930-8149-5134.1Atty. Dkt. No. 144265-0107SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76, the method comprising the steps of:(a) determining whether the cancer ti ssue exhibits HL A-DQ A 1 and / or HL A-DQB 1 high expression, wherein HLA-DQA1 and / or HLA-DQB1 high is defined by a cut point to separate patients with a higher chance of clinical benefit from patients with a lower chance of clinical benefit by a local minimum in biomarker distribution to best separate an HLA-DQA1 and / or HLA-DQB1 high biomarker population when assessed by a qualified or validated assay measuring mRNA levels,(b) if the cancer tissue does not exhibit HLA-DQA1 and / or HLA-DQB1 high expression, excluding the subject from treatment, and(c) if cancer tissue exhibits high HLA-DQA1 and / or high HLA-DQB1 expression, selecting the subject for treatment and administering to the subject having the pancreatic cancer the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76 in combination with the chemotherapy, and optionally the anti-PD-1 antibody or anti-PD-Ll antibody.

[0041] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, the anti-CD-39 antibody is administered in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD-Ll antibody. In some embodiments, the qualified or validated assay measuring mRNA expression levels comprises or consists of PCR. In some embodiments, the qualified or validated assay measuring mRNA levels comprises RT-qPCR or multiplex nucleic acid hybridization technology, such as Nanostring.

[0042] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles. In some embodiments, the anti- PD-1 antibody (e.g., budigalimab) is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.

[0043] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.94930-8149-5134.1Atty. Dkt. No. 144265-0107

[0044] In some embodiments, the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78, and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

[0045] In some embodiments, the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

[0046] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0047] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).

[0048] A sixth aspect provides a method of treating a pancreatic cancer where the genome includes HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 DNA104930-8149-5134.1Atty. Dkt. No. 144265-0107 sequences in a plurality of human subjects, the method comprising or consisting of administering a therapeutically effective amount of an anti-CD39 antibody in combination with chemotherapy, and optionally a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-Ll antibody, to a human subject having the pancreatic cancer, the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76, the method comprising the steps of:(a) determining the presence or absence of the HLA-DQA1*O1 and / or either HLA- DQB1*O5 or HLA-DQB1*O6 DNA sequences in the genome DNA when assessed by a qualified or validated sequencing assay sequencing technology,(b) if the genome does not include the HLA-DQA1*O1 and / or either HLA-DQB1*O5 or HLA-DQB1*O6 DNA sequences, excluding the subject from treatment, and(c) if the genome includes the HLA-DQA1*O1 and / or either HLA-DQB1*O5 or HLA- DQB 1 *06 DNA sequences, selecting the subject for treatment and administering to the subject having the pancreatic cancer the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76 in combination with the chemotherapy, and optionally the anti- PD-1 antibody or anti-PD-Ll antibody.

[0049] In some embodiments, the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel. In some embodiments, the anti-CD-39 antibody is administered in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD-Ll antibody. In some embodiments, the qualified or validated sequencing assay sequencing technology comprises Sanger Sequencing or Next Generation Sequencing.

[0050] In some embodiments, the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles. In some embodiments, the anti- PD-1 antibody (e.g., budigalimab) is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.

[0051] In some embodiments, the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.114930-8149-5134.1Atty. Dkt. No. 144265-0107

[0052] In some embodiments, the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78, and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

[0053] In some embodiments, the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

[0054] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0055] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies).BRIEF DESCRIPTION OF THE DRAWINGS124930-8149-5134.1Atty. Dkt. No. 144265-0107

[0056] FIG. 1 shows HLA-DQB1 gene expression at baseline in patients with pancreatic cancer.

[0057] FIG. 2A shows HLA-DQB1 gene expression at baseline categorized into progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR) for patients treated with chemotherapy + TTX-030 (anti-human CD39 antibody). FIG. 2B shows HLA-DQB1 gene expression categorized into PD, SD, PR, and CR for patients treated with chemotherapy + TTX-030 + anti-PD-1 antibody (budigalimab). FIG. 2C shows aggregate confirmed best overall response (BOR).

[0058] FIG. 3A shows median PFS in patients with high baseline expression of HLA- DQA1 and low baseline expression of HLA-DQA1 receiving chemotherapy + TTX-030 (antihuman CD39 antibody). FIG. 3B shows median PFS in patients with high expression of HLA-DQA1 and low expression of HLA-DQA1 receiving chemotherapy + TTX-030 + anti- PD-1 antibody (budigalimab). FIG. 3C shows median PFS in patients with high expression of HLA-DQA1 and low expression of HLA-DQA1 receiving chemotherapy + TTX-030 + anti- PD-1 antibody (budigalimab) combined with patients receiving chemotherapy + TTX-030.

[0059] FIG. 4A shows PDAC baseline expression for HLA-DQA1. FIG. 4B shows HLA-DQA1 gene expression categorized into PD, SD, PR, and CR for patients treated with chemotherapy + TTX-030 (anti-human CD39 antibody). FIG. 4C shows HLA-DQA1 gene expression categorized into PD, SD, PR, and CR for patients treated with chemotherapy + TTX-030 + anti-PD-1 antibody (budigalimab). FIG. 4D shows aggregate confirmed best overall response (BOR).

[0060] FIG. 5A shows patients that have an HLA-DQAl*01 allele have high HLA- DQA1 gene expression by Nanostring. FIG. 5B shows patients have that have either an HLA- DQBl*05 or HLA-DQB1*O6 allele have high HLA-DQB1 gene expression by Nanostring. FIG. 5C shows best overall response (BOR) categorized by PD, SD, or PR for HLA-DQA1 and FIG. 5D shows BOR categorized by PD, SD, or PR for HLA-DQB 1. FIGs. 5E-G shows PFS by HLA class II genotype in pancreatic cancer grouped by HLA-DQAl*01 vs not HLA- DQAl*01 obtained from peripheral blood. FIG. 5E shows median PFS in patients treated chemotherapy + TTX-030 (anti-human CD39 antibody). FIG. 5F shows median PFS in patients treated with chemotherapy + TTX-030 + anti-PD-1 antibody (budigalimab). FIG. 5G shows a pooled HLA-evaluable PFS. FIGs. 5H-J shows PFS by HLA class II genotype in pancreatic cancer grouped by HLA-DQA1 *01 vs not HLA-DQA1 *01 obtained from peripheral blood. FIG. 5H shows median PFS in patients treated chemotherapy + TTX-030. FIG. 51134930-8149-5134.1Atty. Dkt. No. 144265-0107 shows median PFS in patients treated with chemotherapy + TTX-030 + budigalimab. FIG. 5 J shows a pooled HLA-evaluable PFS.

[0061] FIG. 6 shows phase 1 PDAC patients with HLA-DQhlghhave prolonged OS follow treatment with TTX-030 (anti-human CD39 antibody) combinations.

[0062] FIG. 7 shows an immunohistochemistry schematic.

[0063] FIG. 8 shows improvement in ORR pancreatic cancer patients treated with antihuman CD39 antibody (TTX-030) ± anti-PD-1 antibody (budigalimab), or Gem / NP alone.

[0064] FIG. 9 shows Progression-Free Survival (PFS) Results for pancreatic cancer patients treated with anti-human CD39 antibody (TTX-030) ± anti-PD-1 antibody (budigalimab), or Gem / NP alone.

[0065] FIG. 10 shows Progression-Free Survival (PFS) Results for patients with liver metastasis treated with anti-human CD39 antibody (TTX-030) ± anti-PD-1 antibody (budigalimab), or Gem / NP alone.

[0066] FIG. 11 shows the incidence of treatment-emergent adverse events (TEAE) in pancreatic cancer patients treated with anti-human CD39 antibody (TTX-030) ± anti-PD-1 antibody (budigalimab), or Gem / NP alone.DETAILED DESCRIPTION1 Definitions

[0067] Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0068] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.144930-8149-5134.1Atty. Dkt. No. 144265-0107

[0069] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value.

[0070] The term “combinations thereof’ includes every possible combination of elements to which the term refers.

[0071] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g, Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, Cm, Cm, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0072] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer. As used herein, the term “biomarker” shall mean a measurable substance in an organism whose presence is indicative of some phenomenon, for example a clinical benefit.

[0073] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.154930-8149-5134.1Atty. Dkt. No. 144265-0107

[0074] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0075] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, a, y, and p, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0076] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol.. 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 2621132- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0077] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments. In some embodiments, an antibody that binds CD39, an antibody that binds PD-1, and / or an antibody that binds PD-L1 includes antibody fragments of each of an antibody that binds CD39, an antibody that binds PD-1, and / or an antibody that binds PD-L1.

[0078] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0079] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full-length antibody.

[0080] “F(ab')2” fragments contain two Fab' fragments joined, near the hinge region, by disulfide bonds. F(ab')2 fragments may be generated, for example, by pepsin digestion of an intact antibody. The F(ab') fragments can be dissociated, for example, by treatment with 13- mercaptoethanol.

[0081] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by164930-8149-5134.1Atty. Dkt. No. 144265-0107 a peptide linker. See Pliickthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer- Verlag, New York, incorporated by reference in its entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used.

[0082] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0083] As used herein, the term “plurality” shall refer to a number of things which have distinguishing characteristics not necessarily shared by the whole. For example, without limitation, the genome of a plurality of human subjects may include HLA-DQAl*01 and / or either HLA-DQB 1 *05 or HLA-DQB 1*06 DNA sequences, which sequences are not shared by other human subjects not part of the plurality.

[0084] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.

[0085] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder, such as cancer. In some embodiments, a therapeutically effective comprises or consists of exemplary doses of each antibody. In some174930-8149-5134.1Atty. Dkt. No. 144265-0107 embodiments, a therapeutically effective amount comprises or consists of determining an amount used to achieve a response according to a clinical endpoint. In some embodiments, the clinical endpoint comprises Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS).

[0086] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies), and exhibit stable disease (SD); partial response (PR); or complete response (CR) per RECIST version 1.1.

[0087] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and / or an infection that can be treated with an antibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and / or an acute infection and chronic infection.

[0088] The terms “CD39” and “CD39 antigen” and “Cluster of Differentiation 39” are used interchangeably herein. CD39 is also known as ectonucleoside triphosphate diphosphohydrolase- 1 (gene: ENTPD1; protein: NTPDasel, See www.ncbi.nlm.nih.gov / gene / 953). CD39 has also been referred to as ATPDase and SPG64. Each of the terms set forth above may be used interchangeably. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human CD39 that are naturally expressed by cells, or that are expressed by cells transfected with a CD39 gene.

[0089] The terms “PD-1,” “programmed cell death protein 1,” and “Cluster of Differentiation 279” are used interchangeably herein. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human PD-1 that are naturally expressed by cells, or that are expressed by cells transfected with a PD-1 gene.

[0090] The terms “PD-L1,” “programmed cell death ligand 1,” and “Cluster of Differentiation 724” are used interchangeably herein. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human PD-L1 that are naturally expressed by cells, or that are expressed by cells transfected with a PD-L1 gene.184930-8149-5134.1Atty. Dkt. No. 144265-0107

[0091] As used herein, the term “chemotherapeutic” shall refer to a drug used to treat cancer. Some examples of chemotherapeutics include gemcitabine and nab-paclitaxel (G / nP). Other examples include capecitabine, fluorouracil (5-FU), gemcitabine, Irinotecan or liposomal Irinotecan, leucovorin, Oxaliplatin, or combinations thereof.

[0092] As used herein, “Overall Survival” or “OS” shall refer to the time which begins at diagnosis (or at the start of treatment) and ends at death.

[0093] “Objective Response Rate” or “Overall Response Rate” or “ORR” refers to the percentage of subjects with unconfirmed and confirmed CR or unconfirmed and confirmed PR.

[0094] As used herein, “Progression Free Survival” or “PFS” refers to the time from the participant’s first dose of study treatment to the first date of either disease progression or death, whichever occurs first.

[0095] “Complete Response” or “CR” refers to the disappearance of all target lesions; any pathologic lymph nodes (whether target or nontarget lesions) must have reduction in short axis to less than 10mm.

[0096] “Partial Response” or “PR” refers to at least 30% decrease in the sum of diameters of target lesions; reference is the baseline diameters.

[0097] Stable Disease” or “SD” refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

[0098] “Progressive Disease” or “PD” refers to the at least 20% increase in the sum of the lesion diameter of target lesions or the appearance of one or more new lesions.

[0099] As used herein, “HLA-DQA1” and “major histocompatibility complex, class II, DQ alpha 1” shall mean the human gene present on the short arm of chromosome 6 (6p21.3) which encodes one of the two proteins required for the DQ heterodimer, an essential immune cell surface receptor (See www. genecard.org / cgi -bin / carddisp.pl?gene=HLA-DQAl, which is incorporated by reference in its entirety herein).

[0100] As used herein, “HLA-DQB1” or “major histocompatibility complex, class II, DQ beta 1” shall mean the human gene present on the short arm of chromosome 6 (6p21.32) which encodes the other protein required for the DQ heterodimer See www.genecard.org / cgi- bin / carddisp.pl?gene=HLA-DQBl, which is incorporated by reference in its entirety herein). HLA-DQB1 also belongs to the HLA class II alpha chain paralogues.2 Biomarkers194930-8149-5134.1Atty. Dkt. No. 144265-0107

[0101] Provided herein are methods of treating cancers, such as pancreatic cancers, including certain biomarkers. Biomarkers are a measurable substance in an organism whose presence is indicative of some phenomenon, for example an increased response rate or clinical benefit. The present inventors have found that certain biomarkers expressed in cancers or in the sequence of cancer cells result in increased response rates and / or clinical benefit to certain treatments.

[0102] In some embodiments, the biomarkers comprise or consist of cancer expression of HLA-DQA1 and / or HLA-DQB 1. In some embodiments, the biomarkers comprise or consist of the presence of HLA-DQAl*01 and / or either HLA-DQB 1*05 or HLA-DQB 1*06 DNA in the genome.

[0103] In some embodiments, the biomarkers are measured in samples of blood, tissue, urine, saliva, or other substances in the body. In some embodiments, the level of biomarkers is measured in a tissue sample. In some embodiments, the level of biomarkers is measured in a cancer biopsy. In some embodiments, the level of biomarkers is determined at baseline, meaning before the subject has undergone treatment.

[0104] In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the method includes treating pancreatic cancer in a subject with a pancreatic cancer. In some embodiments, the pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non- metastatic pancreatic cancer.

[0105] In some embodiments, the cancer is characterized by having a high expression of HLA-DQA1 and / or HLA-DQB 1. The expression can be measured when assessed by an assay measuring mRNA expression levels. In some embodiments, the assay is a qualified or validated assay. Qualified or validated assays may include assays that are evidenced as operating accurately and reproducibly. In some embodiments, the qualified or validated assay measuring mRNA expression levels comprises or consists of RT-qPCR or multiplex nucleic acid hybridization technology, such as Nanostring.

[0106] In some embodiments, the method comprises determining whether the cancer tissue exhibits HLA-DQA1 and / or HLA-DQB 1 high expression. In some embodiments, a high expression of HLA-DQA1 and / or HLA-DQB 1 is defined by a cut point (See Determination of cutoff values for biomarkers in clinical studies, Precision and Future Medicine 2020; 4(1): 2- 8, which is incorporated by reference in its entirety herein).204930-8149-5134.1Atty. Dkt. No. 144265-0107

[0107] In some embodiments, the cut point is defined by a local minimum in biomarker distribution to best separate an HLA-DQA1 or HLA-DQB1 high biomarker population from an HLA-DQA1 or HLA-DQB1 low biomarker population. In some embodiments, the expression of HLA-DQA1 or HLA-DQB1 is assessed by a qualified or validated assay measuring mRNA levels. In some embodiments, the qualified or validated assay measuring mRNA levels includes RT-qPCR or multiplex nucleic acid hybridization technology, such as Nanostring.

[0108] In some embodiments, the method comprises excluding the subject from treatment if the cancer tissue does not exhibit a high expression of HLA-DQA1 and / or HLA- DQB 1. In some embodiments, the method comprises selecting the subject for treatment if the cancer tissue exhibits a high expression of HLA-DQA1 and / or HLA-DQB1. In some embodiments, the method comprises administering an anti-CD39 antibody in combination with a chemotherapy, and optionally an anti-PD-1 antibody or anti-PD-Ll antibody to the subject selected for treatment.

[0109] In some embodiments, the method comprises determining the presence or absence of the HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 DNA in the genome. In some embodiments, the presence or absence of HLA-DQAl*01 and / or either HLA-DQB 1 *05 or HLA-DQB 1*06 DNA in the genome is assessed by a qualified or validated sequencing assay technology. In some embodiments, the qualified or validated sequencing technology comprises Sanger Sequencing or Next Generation Sequencing.

[0110] In some embodiments, the method comprises excluding the subject from treatment if the genome does not include HLA-DQAl*01 and / or either HLA-DQB 1*05 or HLA-DQB 1*06 DNA. In some embodiments, the method comprises selecting the subject for treatment if the genome includes the HLA-DQAl*01 and / or either HLA-DQB 1*05 or HLA- DQB 1*06 DNA sequences.3 Treatment[OHl] In some embodiments, the method comprises administering a compound to the subject. In some embodiments, the method comprises or consists of administering to the subject an antibody specific for CD39. In some embodiments, the method comprises or consists of administering to the subject one or more of an antibody specific for CD39, an antibody specific for PD-1 and / or PD-L1, and / or a chemotherapeutic. In some embodiments,214930-8149-5134.1Atty. Dkt. No. 144265-0107 the method comprises or consists of administering an anti-CD-39 antibody in combination with chemotherapy.

[0112] In some embodiments, the method further includes administering an anti-PD-1 antibody in combination with the anti-CD-39 antibody and / or the chemotherapy. In some embodiments, the method further includes administering an anti-PDL-1 antibody in combination with the anti-CD-39 antibody and / or the chemotherapy. In some embodiments, the method further includes administering an anti-PD-1 antibody and an anti-PD-Ll antibody in combination with the anti-CD-39 antibody and / or the chemotherapy.

[0113] In some embodiments, the antibody specific for CD39 is TTX-030 and comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence set forth in SEQ ID NO: 11, and a VHCDR3 having the sequence set forth in SEQ ID NO: 21. In some embodiments, the antibody specific for CD39 is TTX-030 and has a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 31, a VLCDR2 having the sequence set forth in SEQ ID NO: 39, and a VLCDR3 having the sequence set forth in SEQ ID NO: 47.

[0114] In some embodiments, the antibody specific for CD39 is TTX-030 and comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 56 and the light chain variable region comprising or consisting of a molecule having a sequence comprising or consisting of SEQ ID NO: 66. In some embodiments, the antibody specific for CD39 is TTX-030 and comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 75 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 76.

[0115] In some embodiments, the method comprises administering an antibody specific for PD-1, such as budigalimab, nivolumab, or pembrolizumab. In some embodiments, the method comprises administering an antibody specific for PD-L1, such as atezolizumab, avelumab, and / or durvalumab.

[0116] In some embodiments, the antibody specific for PD-1 is budigalimab. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable224930-8149-5134.1Atty. Dkt. No. 144265-0107 region comprising or consisting of a VHCDR1 having the sequence set forth in SEQ ID NO: 2, a VHCDR2 having the sequence set forth in SEQ ID NO: 12, and a VHCDR3 having the sequence set forth in SEQ ID NO: 22. In some embodiments, the antibody specific for PD-1 comprises or consists of a light chain variable region comprising or consisting of a VLCDR1 having the sequence set forth in SEQ ID NO: 30, a VLCDR2 having the sequence set forth in SEQ ID NO: 38, and a VLCDR3 having the sequence set forth in SEQ ID NO: 46.

[0117] In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 57 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 65. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 77 or SEQ ID NO: 78 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 79.

[0118] In some embodiments, the antibody specific for PD-1 is nivolumab. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 3, a VHCDR2 having the sequence set forth in SEQ ID NO: 13, and a VHCDR3 having the sequence set forth in SEQ ID NO: 23. In some embodiments, the antibody specific for PD-1 comprises or consists of a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 32, a VLCDR2 having the sequence set forth in SEQ ID NO: 40, and a VLCDR3 having the sequence set forth in SEQ ID NO: 48.

[0119] In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 58 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 67. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 80 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 81.234930-8149-5134.1Atty. Dkt. No. 144265-0107

[0120] In some embodiments, the antibody specific for PD-1 is pembrolizumab. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 4, a VHCDR2 having the sequence set forth in SEQ ID NO: 14, and a VHCDR3 having the sequence set forth in SEQ ID NO: 24. In some embodiments, the antibody specific for PD-1 has a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 33, a VLCDR2 having the sequence set forth in SEQ ID NO: 41, and a VLCDR3 having the sequence set forth in SEQ ID NO: 49.

[0121] In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 59 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 68. In some embodiments, the antibody specific for PD-1 comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 82 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 83.

[0122] In some embodiments, the antibody specific for PD-L1 is atezolizumab. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 5, a VHCDR2 having the sequence set forth in SEQ ID NO: 15, and a VHCDR3 having the sequence set forth in SEQ ID NO: 25. In some embodiments, the antibody specific for PD-L1 has a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 34, a VLCDR2 having the sequence set forth in SEQ ID NO: 42, and a VLCDR3 having the sequence set forth in SEQ ID NO: 50.

[0123] In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 60 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 69. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain and a light chain, the heavy244930-8149-5134.1Atty. Dkt. No. 144265-0107 chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 84 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 85.

[0124] In some embodiments, the antibody specific for PD-L1 is avelumab. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 6, a VHCDR2 having the sequence set forth in SEQ ID NO:16, and a VHCDR3 having the sequence set forth in SEQ ID NO: 26. In some embodiments, the antibody specific for PD-L1 has a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 35, a VLCDR2 having the sequence set forth in SEQ ID NO: 43, and a VLCDR3 having the sequence set forth in SEQ ID NO: 51.

[0125] In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 61 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 70. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 86 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 87.

[0126] In some embodiments, the antibody specific for PD-L1 is durvalumab. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region, the heavy chain variable region comprises or consists of a VHCDR1 having the sequence set forth in SEQ ID NO: 7, a VHCDR2 having the sequence set forth in SEQ ID NO:17, and a VHCDR3 having the sequence set forth in SEQ ID NO: 27. In some embodiments, the antibody specific for PD-L1 has a light chain variable region, the light chain variable region comprises or consists of a VLCDR1 having the sequence set forth in SEQ ID NO: 36, a VLCDR2 having the sequence set forth in SEQ ID NO: 44, and a VLCDR3 having the sequence set forth in SEQ ID NO: 52.

[0127] In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting254930-8149-5134.1Atty. Dkt. No. 144265-0107 of SEQ ID NO: 62 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 71. In some embodiments, the antibody specific for PD-L1 comprises or consists of a heavy chain and a light chain, the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 88 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 89.

[0128] In some embodiments, the chemotherapeutic comprises or consists of gemcitabine. In some embodiments, the chemotherapeutic comprises or consists of nab- paclitaxel. In some embodiments, the chemotherapeutic comprises or consists of a combination of gemcitabine and nab-paclitaxel. In some embodiments, the chemotherapeutic comprises or consists of capeci tabine, fluorouracil (5-FU), gemcitabine, Irinotecan or liposomal Irinotecan, leucovorin, Oxaliplatin, or combinations thereof.

[0129] Compounds for each of the respective antibodies and chemotherapeutics will contain one or more active agents and may further contain solvents, buffers, diluents, carriers, and other excipients to aid the administration, solubility, absorption or bioavailability, and / or stability, etc. of the active agent(s) or overall composition. Each of the antibodies and chemotherapeutics can be provided in an appropriate pharmaceutical composition and administered by any suitable route of administration. Suitable routes of administration for each of the antibodies and chemotherapeutics include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. Each composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.4 Dosing

[0130] The doctor will determine the dose which they consider most appropriate according to age, weight, condition, and other factors specific to the subject being administered the compound, including available guidance on recommend dosages.

[0131] In some embodiments, the antibody specific for CD39 is administered at a dosage from 0.5 mg / kg to 60 mg / kg. In some embodiments, the antibody specific for264930-8149-5134.1Atty. Dkt. No. 144265-0107CD39 is administered at a dosage from 0.5 mg / kg to 1 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 1 mg / kg to 5 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 5 mg / kg to 10 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 10 mg / kg to 15 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 15 mg / kg to 20 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 20 mg / kg to 25 mg / kg. In some embodiments, antibody specific for CD39 is administered at a dosage from 25 mg / kg to 30 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 30 mg / kg to 35 mg / kg. In some embodiments, antibody specific for CD39 is administered at a dosage from 35 mg / kg to 40 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 40 mg / kg to 45 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 45 mg / kg to 50 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 50 mg / kg to 55 mg / kg. In some embodiments, the antibody specific for CD39 is administered at a dosage from 55 mg / kg to 60 mg / kg.

[0132] In some embodiments, the antibody specific for CD39 is administered at a dosage of 40mg / kg (as a loading dose) and then 20 mg / kg every two weeks. In some embodiments, the antibody specific for CD39 is administered at a dosage of 20 mg / kg every two weeks. In some embodiments, the antibody specific for CD39 is administered at a dosage of 10 mg / kg every two weeks. In some embodiments, the antibody specific for CD39 is administered at a dosage of 30 mg / kg every two weeks. In some embodiments, the antibody specific for CD39 is administered at a dosage of 30 mg / kg every three weeks.

[0133] In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage from Img to 1 g. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 50 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 100 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 150 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 200 mg. In some embodiments, the antibody specific for PD- 1 and / or PD-L1 is administered at a dosage of 250 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 300 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of274930-8149-5134.1Atty. Dkt. No. 144265-0107350 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 400 mg. In some embodiments, the antibody specific for PD- 1 and / or PD-L1 is administered at a dosage of 450 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 500 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of550 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 600 mg. In some embodiments, the antibody specific for PD- 1 and / or PD-L1 is administered at a dosage of 650 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 700 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 750 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 800 mg. In some embodiments, the antibody specific for PD- 1 and / or PD-L1 is administered at a dosage of 850 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of 900 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of950 mg. In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered according to its prescribing information.

[0134] In some embodiments, the antibody specific for PD-1 and / or PD-L1 is administered at a dosage of lOOOmg q6w maintenance.

[0135] In some embodiments, the chemotherapeutic comprises or consists of gemcitabine. In some embodiments, the chemotherapeutic is administered at a dosage of 500 mg / m2to 1500 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 500 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 600 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 700 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 800 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 900 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1000 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1200 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1300 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1400 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1500 mg / m2.284930-8149-5134.1Atty. Dkt. No. 144265-0107

[0136] In some embodiments, the chemotherapeutic is administered at a dosage of1250 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 1000 mg / m2. In some embodiments, the dosage is reduced and the chemotherapeutic is administered twice at a dosage of 750-800 mg / m2and then once at 500-600 mg / m2.

[0137] In some embodiments, the chemotherapeutic comprises or consists of nab- paclitaxel. In some embodiments, the chemotherapeutic is administered at a dosage of 50 mg / m2to 200 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 50 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 75 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 100 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 125 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 175 mg / m2. In some embodiments, the chemotherapeutic is administered at a dosage of 200 mg / m2.

[0138] In some embodiments, the chemotherapeutic is administered at a dosage of 260 mg / m2every three weeks. In some embodiments, the chemotherapeutic is administered at a dosage of 100 mg / m2weekly. In some embodiments, the chemotherapeutic is administered at a dosage of 125 mg / m2on day 1, 8, and 15 of 28day cycles. In some embodiments, the chemotherapeutic is administered at a dosage with a dose reduction, wherein the dose reduction is 120 mg / m2, 100 mg / m2, 50 mg / m2, or 75 mg / m2.5 Scheduling

[0139] The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy administered as well as age, body, weight, response, and the past medical history of the subject. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0140] In some embodiments, the combination is assembled in the subject being treated, whether they are administered at the same time or different times. In some embodiments, the components of the combination are mixed together at the point of care prior to administration.

[0141] In some embodiments, the CD39 antibody, PD-1 antibody, and / or PD-L1 antibody, and / or chemotherapy are administered on the same schedule. In some embodiments, the CD39 antibody, PD-1 antibody, and / or PD-L1 antibody, and / or chemotherapy are294930-8149-5134.1Atty. Dkt. No. 144265-0107 administered on a different schedule. In some embodiments, the CD39 antibody and PD-1 antibody and / or PD-L1 antibody are administered on the same schedule but the chemotherapy is administered on a different schedule.

[0142] In some embodiments, the CD39 antibody is administered once a week. In some embodiments, the CD39 antibody is administered every other week. In some embodiments, the CD39 antibody is administered every three weeks. In some embodiments, the CD39 antibody is administered every four weeks. In some embodiments, the CD39 antibody is administered every five weeks. In some embodiments, the CD39 antibody is administered every six weeks. In some embodiments, the CD39 antibody is administered every seven weeks. In some embodiments, the CD39 antibody is administered every eight weeks.

[0143] In some embodiments, the dose and dosing frequency of the CD39 antibody is 20 mg / kg every two weeks. In some embodiments, the dose and dosing frequency of the CD39 antibody is 30 mg / kg every three weeks. In some embodiments, the dose and dosing frequency of the CD39 antibody is 40 mg / kg every four weeks.

[0144] In some embodiments, the PD-1 and / or PD-L1 antibody is administered once a week. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every other week. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every three weeks. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every four weeks. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every five weeks. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every six weeks. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every seven weeks. In some embodiments, the PD-1 and / or PD-L1 antibody is administered every eight weeks.

[0145] In some embodiments, the dose and dosing frequency of the PD-1 and / or PD- L1 antibody is between 100 mg and 300 mg every week. In some embodiments, the dose and dosing frequency of the PD- 1 and / or PD-L1 antibody is between 200 mg and 400 mg every two weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 300 mg and 500 mg every three weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 400 mg and 600 mg every four weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 500 mg and 700 mg every five weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 600 mg and 800 mg every six weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 700 mg and 900 mg every304930-8149-5134.1Atty. Dkt. No. 144265-0107 seven weeks. In some embodiments, the dose and dosing frequency of the PD-1 and / or PD-L1 antibody is 800 mg and 1 g every eight weeks.

[0146] In some embodiments, the anti-human CD39 antibody is administered on days 1 and 15 of a 28-day cycle. In some embodiments, the anti-PDl and / or anti-PD-Ll antibody is administered to the subject every four weeks, such as on day 1 of a 28-day cycle. In some embodiments, the anti-PDl (e.g., budigalimab) and / or anti-PD-Ll antibody is administered to the subject every four weeks at a dosage of 500 mg. In some embodiments, chemotherapy is administered on days 1, 8, and 15 of a 28-day cycle. In some embodiments, gemcitabine is administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of a 28-day cycle. In some embodiments, nab-paclitaxel is administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of a 28-day cycle.

[0147] In some embodiments, the anti-CD-39 antibody is administered before the administration of the chemotherapy. In some embodiments, the anti-CD-39 antibody is administered after the administration of the chemotherapy.

[0148] In some embodiments, the anti-PD-1 and / or anti-PD-Ll antibody is administered after the administration of the anti-CD-39 antibody. In some embodiments, the anti-PD-1 and / or anti-PD-Ll antibody is administered before the administration of the anti- CD-39 antibody. In some embodiments, the anti-PD-1 and / or anti-PD-Ll antibody is administered before the administration of the chemotherapy. In some embodiments, the anti- PD-1 and / or anti-PD-Ll antibody is administered after the administration of the chemotherapy.

[0149] In some embodiments, the dosing regimen further comprises an initial loading dose of anti-CD-39 antibody. In some embodiments, the initial loading comprises 40 mg / kg one week before beginning a repetitive portion of a dosing regimen (maintenance doses).

[0150] In some embodiments, the dosing regimen further comprises an initial loading dose of anti-CD-39 antibody between 10 mg / kg and 90 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 10 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 20 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 30 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 40 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 50 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 60 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 70 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 80 mg / kg. In some embodiments, the loading dose of anti-CD-39 antibody is 90 mg / kg.314930-8149-5134.1Atty. Dkt. No. 144265-0107

[0151] In some embodiments, the dosing regimen comprises or consists of the dosing regimen set forth in the examples and / or the specification.6 Clinical Benefit

[0152] In some embodiments a response in the subject is measured. Any method can be used to assess response. Some embodiments provide for assessing response using RECIST criteria (See, https: / / recist.eortc.org / recist-l-l-2 / and new response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), European Journal of Cancer 45 (2009) 228- 247, incorporated by reference in their entirety herein).

[0153] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS) and / or progression-free survival (PFS). In some embodiments, the treatment provides an objective response rate (ORR) that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has a PFS that is superior to that of a standard of care therapy(ies). In some embodiments, pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer comprises non-metastatic pancreatic cancer.

[0154] Treated subjects should achieve one or more of the following clinical endpoints as compared to standard of care therapy(ies): overall response rate (ORR) greater than about 10% as compared to standard of care therapy(ies); a median duration of response (DoR) of at least 2 months longer than standard of care therapy(ies); progression free survival (PFS) at least 2 months longer as compared to standard of care therapy(ies); or overall survival (OS) at least 2 months longer than standard of care therapy(ies), and exhibit stable disease (SD); partial response (PR); or complete response (CR) per RECIST version 1.1.

[0155] Different methods may be used to measure a tumor. Some internal cancer tumors will show up on an x-ray or CT scan and can be measured with a ruler. Blood tests, including those that measure organ function can be performed. A tumor marker test can be done for certain cancers.

[0156] In some embodiments, the response is measured according to complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Under the RECIST criteria, CR is the disappearance of all target lesions; any pathologic lymph nodes (whether target or nontarget lesions) must have reduction in short axis to less than 10mm. Under the RECIST criteria, PR is an at least 30% decrease in the sum of diameters of target lesions compared to the reference of the baseline diameters. Under the RECIST criteria, stable324930-8149-5134.1Atty. Dkt. No. 144265-0107 disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum lesion diameter since the treatment started. Lastly, under the RECIST criteria, PD is the at least 20% increase in the sum of the lesion diameter of target lesions or the appearance of one or more new lesions. In some embodiments, the treatment will provide a CR or PR in subjects with a high expression of HLA-DQA1 and / or HLA-DQB1. In some embodiments, the treatment will provide a CR or PR in subjects with HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 in the genome.

[0157] In some embodiments, the clinical benefit is measured according to overall survival. Overall survival or OS refers to the time from treatment to death. Overall survival is one important data point for both patients and their physicians to use as an indication of how well a treatment works. Survival rates can be described for any period of time. A five-year survival rate is often employed.

[0158] In some embodiments, the clinical benefit is measured according to the ORR. The ORR refers to the percentage of subjects with unconfirmed and confirmed CR or unconfirmed and confirmed PR.

[0159] In some embodiments, subjects with a high expression of HLA-DQA1 and / or HLAD-QB1 have an increased ORR relative to subjects with a low expression of HLA-DQA1 and / or HLAD-QB1. In some embodiments, subjects with a high expression of HLA-DQA1 and / or HLADQ-B1 have an ORR greater than about 40%, greater than about 45%, or greater than about 50% as compared to standard of care therapies.

[0160] In some embodiments, subjects with HLA-DQAl*01 and / or either HLA- DQBl*05 or HLA-DQB1*O6 in the genome have an increased ORR relative to subjects without HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 in the genome. In some embodiments, subjects with HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA- DQB1*O6 in the genome have an ORR greater than about 40%, greater than about 45%, or greater than about 50% as compared to standard of care therapies.

[0161] In some embodiments, the clinical benefit is measured according to progression free survival (PFS). PFS refers to the time from the participant’s first dose of treatment to the first date of either disease progression or death, whichever occurs first.

[0162] In some embodiments, subjects with a high expression of HLA-DQA1 and / or HLAD-QB1 have an increased PFS relative to subjects with a low expression of HLA-DQA1 and / or HLAD-QB1. In some embodiments, subjects with a high expression of HLA-DQA1334930-8149-5134.1Atty. Dkt. No. 144265-0107 and / or HLAD-QB1 have a PFS greater than about 6 months, greater than about 7 months, greater than about 8 months, greater than about 9 months, or greater than about 10 months.

[0163] In some embodiments, subjects with HLA-DQAl*01 and / or either HLA- DQBl*05 or HLA-DQB1*O6 DNA sequences in the genome have an increased PFS relative to subjects without HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 DNA sequences in the genome. In some embodiments, subjects with HLA-DQAl*01 and / or either HLA-DQBl*05 or HLA-DQB1*O6 DNA sequences in the genome have a PFS greater than about 6 months, greater than about 7 months, greater than about 8 months, greater than about 9 months, or greater than about 10 months.EXAMPLESExample 1: Phase 1 Inclusion and Exclusion and Dose Identification of Anti human CD39 Antibody in Combination with Chemotherapy with or without Anti human PD-1 antibody in Subjects with Locally Advanced Unresectable or Metastatic Pancreatic Cancer

[0164] Inclusion criteria included male or female subjects >18 years of age at the time of screening (or for South Korea: >19 years of age at the time of screening), fresh and / or archival tumor tissue unless contraindicated, evidence of measurable disease by computed tomography (CT), CT-positron emission tomography (PET), or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a life expectancy >12 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0165] Inclusion criteria also included adequate organ and marrow function, defined as: a. Absolute neutrophil count >1.5 k / pL, platelets >75 k / pL (platelets >100 k / pL for chemotherapy arms), hemoglobin >8 g / dL (hemoglobin >9 g / dL for chemotherapy arms). b. Serum creatinine <1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) 2::40 mL / min. NOTE: Subjects eligible for cohort 10 may have CrCl <40 mL / min after approval by the medical monitor. c. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <2.5 x ULN (or <5 x ULN with hepatic metastases). d. Total bilirubin <2 x ULN (or <3 x ULN with Gilbert's syndrome).344930-8149-5134.1Atty. Dkt. No. 144265-0107 e. Prothrombin time (PT) / international normalized ratio (INR.) and activated partial thromboplastin time (aPTT) <1.2 x ULN; fibrinogen >150 mg / dL. f. Serum albumin >3.0 g / dL.Subjects also had to have at least 14 days since last dose of chemotherapy or biological therapy or tyrosine kinase inhibitor or high-dose (e.g.,> 10 mg prednisone or equivalent per day) steroid therapy prior to the loading dose / first dose of study treatment. Resolution of adverse effects from any prior chemotherapy, immunotherapy, or prior systemic anticancer therapy, radiotherapy, or surgery to Grade 1 or baseline (except Grade 2 alopecia and Grade 2 sensory neuropathy) were also required. Subjects with a history of congestive heart failure were required to have a cardiac echocardiogram or multigated acquisition scan indicating left ventricular ejection fraction >45% within 21 days prior to the loading dose / first dose of study treatment.

[0166] Inclusion criteria also included the requirement for histologically or cytologically confirmed diagnosis of locally advanced, unresectable or metastatic pancreatic adenocarcinoma. No prior treatment for metastatic disease and no prior (neo-) adjuvant therapy within 6 months of study enrollment were allowed.

[0167] Exclusion criteria included a history of allergy or hypersensitivity to the study treatment components. Subjects with a history of severe hypersensitivity reaction to any monoclonal antibody (defined as any Grade 3 reaction lasting >48 hours despite optimal therapy) were excluded. Subjects that used an investigational agent within fourteen (14) days prior to the loading dose / first dose of study treatment and throughout the study, chemotherapy, radiation therapy, biologic therapy, herbal therapy, or any investigational therapy within 14 days prior to the loading dose / first dose of study treatment were excluded. Palliative radiation therapy to non-target lesions was allowed.

[0168] Subjects were excluded that received high-dose (e.g., >10 mg prednisone or equivalent per day) systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the loading dose / first dose of study treatment; however, inhaled, intranasal, intraocular, topical, and intraarticular steroids were allowed. Transient steroid administration as anti-emetic or chemotherapy pre-conditioning (e.g., for paclitaxel) was also allowed. Subjects that received therapeutic anticoagulation were excluded. Prophylactic anti coagulation with low-molecular- weight heparin, Factor Xa inhibitors, and low-dose aspirin354930-8149-5134.1Atty. Dkt. No. 144265-0107 was allowed. Patients with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease) requiring systemic treatment or transplant that requires systemic steroids or immunosuppressive agents within the last 2 years were excluded. Patients with a history of vitiligo, autoimmune thyroiditis, or mild psoriasis were allowed.

[0169] Subjects with a known history of HIV or other chronic immunodeficiency were excluded. Also, subjects with an uncontrolled intercurrent illness were excluded, the illnesses including, but not limited to:• Uncontrolled diabetes.• Ongoing or active bacterial, viral, or fungal infection requiring systemic treatment.• Clinically significant congestive heart failure defined by New York Heart Association Class 3 or Class 4.• Unstable angina, arrhythmia, or myocardial infarction within 6 months prior to screening.• Uncontrolled tumor-related pain. (Subjects requiring narcotic pain medication had to be on a stable regimen at study entry).• Poorly controlled hypertension, defined as a blood pressure consistently above 150 / 90 mmHg despite optimal medical management.• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX@) were allowed.• Active or chronic viral hepatitis B or C infection. Subjects who were positive for hepatitis B surface antigen or hepatitis C antibody were excluded. If hepatitis B core antibody was positive, the subject had to have a negative PCR result before enrollment. Those who are PCR positive were excluded.• Uncontrolled thyroid disease.• Known history of active tuberculosis.• Active infection requiring systemic therapy (Grade ~2) for more than 3 days within I week of dosing.

[0170] Subjects with active or untreated central nervous system metastases were excluded. Subjects with brain metastases were eligible provided they were able to show clinical364930-8149-5134.1Atty. Dkt. No. 144265-0107 and radiographic SD for at least 4 weeks after definitive therapy and had not used steroids (> 10 mg / day of prednisone or equivalent) for at least 4 weeks prior to the loading dose / first dose of study treatment. Subjects with a history of any other malignancy within the past 3 years were excluded (except for successfully treated non-melanoma skin cancer or localized carcinoma in situ that is considered cured or adequately treated by the investigator). Subjects with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer were eligible.

[0171] Women who were pregnant or breastfeeding were excluded. Subjects that received a live vaccine within 28 days prior to the loading dose / first dose of study drug were excluded. Subjects with a history of (except in the setting of PD-(L)1 therapy) or ongoing pneumonitis or interstitial lung disease and history of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis were excluded. Subjects who had been previously treated with an anti PD-(L)1 targeting agent were excluded if they had any of the following during the course of their therapy: a. Any immune-mediated toxicity of Grade 3 or worse severity. b. Any ocular or neurologic toxicity. c. Any hypersensitivity to PD-(L)1 targeting agents for subjects in the budigalimab and pembrolizumab-containing cohorts.

[0172] Subjects judged by the investigator to have evidence of ongoing hemolysis on hemolysis panel (total, direct and unconjugated serum bilirubin, peripheral blood smear, D- dimers, and serum haptoglobin) were excluded. Subjects that had major surgery per the investigator within 28 days prior to the loading dose / first dose of study drug, and the surgical wound is not fully healed were excluded. A diagnostic or research biopsy did not exclude subjects from enrollment and placement of a vascular access device such as a Port-A-Cath was not considered major surgery. Subjects with a history of major immunologic reaction (Grade 3-4) to any IgG-containing agent were excluded. Subjects with a history of primary immunodeficiency, bone marrow transplantation, chronic lymphocytic leukemia, solid organ transplantation, or previous clinical diagnosis of tuberculosis were excluded. Subjects with a history of Stevens- Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) were excluded.

[0173] Two study treatment regimens were evaluated in a total of 57 efficacy-evaluable study participants with pancreatic adenocarcinoma:374930-8149-5134.1Atty. Dkt. No. 144265-01071. Gem / NP + anti-human CD39 antibody (“doublet”)2. Gem / NP + anti-human CD39 antibody + budigalimab (“triplet”)Gemcitabine (1000 mg / m2) / nab-paclitaxel (125 mg / m2) (i.e., G / NP) was administered on Days 1,8, and 15 of each 28-day treatment cycle according to standard clinical practice.

[0174] The anti-human CD39 antibody (i.e., TTX-030) was administered intravenously at 40 mg / kg over at least 60 minutes on Day -7 (loading dose), and then at 20 mg / kg before the administration of chemotherapy on Days 1 and 15 of each 28-day treatment cycle.

[0175] The budigalimab (i.e., the anti-human PD-1) antibody was administered intravenously at 500 mg over at least 60 minutes on Day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.Example 2: Baseline expression of HLA-DQB1 is correlated with increased clinical responses in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab

[0176] Fresh and / or archival tumor biopsy tissues were submitted as formalin-fixed, paraffin embedded (FFPE) blocks, or FFPE slides. Biopsies were collected and processed per institutional guidelines and procedures for the procurement of fresh tumor biopsy samples. Archival tissue collected within ninety (90) days prior to first dose was accepted if there had been no intervening therapy.

[0177] RNA was extracted from FFPE tissue slides using MagMAX™ FFPE DNA / RNAUltra Kit (ThermoFisher, Waltham, MA) according to the manufacturer's protocols. Paraffin was removed from the slides and tissue was digested with protease. RNA was manually isolated from the digested tissue using magnetic beads and centrifugation and purified RNA was collected following DNase treatment.

[0178] Gene expression analysis of tumor tissues was analyzed using a nCounter® PanCancer Immune Profiling Panel on an nCounter Analysis System (Nanostring, Seattle, WA).

[0179] HLA-DQB1 gene expression at baseline obtained from tumor biopsies in pancreatic cancer clusters into high and low is shown in FIG. 1. Expression is depicted as normalized gene expression. The dotted line at a value of -2.02 is an example of a cut-point based on HLA-DQB1 expression of the mean + 2*StDev of HLA-DQlowpancreatic patients. FIG. 2A shows HLA-DQB 1 gene expression at baseline in patients with pancreatic cancer prior384930-8149-5134.1Atty. Dkt. No. 144265-0107 to treatment. FIG. 2C again shows HLA-DQB1 gene expression at baseline in patients with pancreatic cancer prior to treatment, with 29 / 40 being, representing 72.5%, being above the cut-point.

[0180] The efficacy analysis was based on the efficacy-evaluable population of study participants and the documented investigator-assessed tumor response according to published and internationally accepted guidelines. In the following, reference is made only to assessments according to RECIST version 1.1. All efficacy data referred to were based on data extract from the trial data bases dated 05Dec2023.• The objective response rate (ORR) was defined as the sum of the confirmed partial responses (PRs) and complete responses (CRs) divided by the number of efficacy- evaluable study participants.• The progression-free survival (PFS) is defined as the time from the date of initiation of study treatment until the first assessment of progressive disease (PD). Censoring rules were applied as follows: o at the time of last evaluable tumor assessment in the absence of documented disease progression or death o at the time of last evaluable tumor assessment if alternative anti -tumor therapy was started in the absence of documented disease progression.

[0181] HLA-DQB1 gene expression at baseline obtained from tumor biopsies in pancreatic cancer is correlated with clinical response, as shown in FIGs. 2A-C. Expression is depicted as normalized gene expression for patients treated with chemotherapy + TTX-030 (FIG. 2 A) and for patients treated with chemotherapy + TTX-030 + budigalimab (FIG. 2B), grouped by best overall response (PD = progressive disease, SD = stable disease, PR = partial response, CR = complete response). The dotted line at a value of -2.02 is an example of a cutpoint based on HLA-DQB1 expression of the mean + 2*StDev of HLA-DQlowpancreatic patients. Patients above this cutoff are considered HLA-DQhlgh, patients below this cutoff are considered HLA-DQlow. HLA-DQhlghwas statistically correlated with clinical response (either PR or CR) in pancreatic cancer patients receiving chemotherapy + TTX-030 and in patients receiving chemotherapy + TTX-030 + / - budigalimab. FIG. 2C shows PDAC aggregate confirmed best overall response.

[0182] Pancreatic cancer patients with HLA-DQAlhlghat baseline have a higher rate of confirmed clinical responses (PR or CR) following treatment with chemotherapy + TTX-030394930-8149-5134.1Atty. Dkt. No. 144265-0107+ / - budigalimab than patients with HLA-DQlowat baseline, as depicted in in Table 1. Increased clinical response rates in HLA-DQAlhlghbaseline biopsies were observed in patients receiving either chemotherapy + TTX-030 (43% versus 13%, respectively) or chemotherapy + TTX-030 + budigalimab (50% versus 0%), or when considering patients receiving either regimen (46% versus 8%).BiomarkerEvahabteORR by group (%) By NanoSfrbg* HLA»DQA1h^hHLA~DQA1to*TTX-030+G / nP (PD AC)(Arm 4 + Cohort 1 1 )TTX-030+budi+G / nP (PDAC)(Cohort ?) n — i oCombined PDAC*Data set includes efficacy-evaluable patients with NanoString results Data cut-off date 05Dec2023Table 1Example 3: Baseline expression of HLA-DQA1 is correlated with prolonged PFS in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab

[0183] Median progression free survival was assessed per RECIST version 1.1.

[0184] Pancreatic cancer patients with HLA-DQAlhlghat baseline demonstrated an increased median progression free survival following treatment with chemotherapy + TTX-030 + / - budigalimab as opposed to patients with HLA-DQAllowat baseline, as depicted in FIGs.3 A- C and Table 2. Median PFS in patients receiving chemotherapy + TTX-030 was 9.4 months for patients with HLA-DQAlhlghbaseline biopsies versus 3.7 months for HLA-DQAllowpatients (FIG. 3 A). Median PFS in patients receiving chemotherapy + TTX-030 + budigalimab was 9.6 months for patients with HLA-DQAlhlghbaseline biopsies versus 5.4 months for HLA-404930-8149-5134.1Atty. Dkt. No. 144265-0107DQAllowpatients (FIG. 3B). Combined analysis of patients receiving chemotherapy + TTX- 030 + / - budigalimab demonstrated that median PFS was 9.6 months for patients with HLA- DQAlhlghbaseline biopsies versus 5.2 months for HLA-DQAllowpatients (FIG. 3C).#Data set includes efficacy-evaluable patients with NanoString results Data cut-off date 05Dec2023Table 2Example 4: Baseline expression of HLA-DQA1 is correlated with increased clinical responses in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab

[0185] HLA-DQA1 gene expression at baseline obtained from tumor biopsies in pancreatic cancer is shown in FIG. 4A. Expression is depicted as normalized gene expression for patients treated with chemotherapy + TTX-030 (FIG. 4B) and for patients treated with chemotherapy + TTX-030 + budigalimab (FIG. 4C) grouped by best overall response. FIG. 4D shows PDAC aggregate confirmed best objective response (BOR).Example 5: HLA-DQA1 *01 genotype is correlated with prolonged PFS in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab

[0186] Whole blood was collected in Cell-Free DNA BCT tube (Streck, La Vista, Nebraska). The tube was processed per the manufacturer’s instructions to collect plasma and buffy coats, which were then both stored frozen.

[0187] DNA was extracted from the banked buffy coat samples.

[0188] Sequencing was performed at LabCorp for four field HLA class II genotyping using a long-range Next Generation Sequencing (NGS) assay performed on a PacBio Sequel414930-8149-5134.1Atty. Dkt. No. 144265-0107((PacBio, Menlo Park, CA). HLA-DRB1, DRB345, DQB1, DPB1, DPA1, and DQA1 were assayed, and results reported. The sequencing approach provides gene coverage of Exons 2,3,4 and reporting format is up to four field resolution. In addition, a parallel NGS assay was performed and compared against the PacBio assay for concordance. The parallel assay targets the antigen recognition domain (ARD) region which is encoded in exon 2 only.

[0189] Pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab are grouped by HLA-DQA1 genotype and HLA-DQA1 high and low expression by Nanostring. Patients with HLA-DQAl*01 genotype are HLA-DQAlhlghby Nanostring as depicted in FIG 5 A. Patients with either HLA-DQB 1 *05 or HLA-DQB 1*06 genotype are also HLA-DQBlhlghby Nanostring as depicted in FIG 5B.

[0190] Pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab are grouped by HLA-DQA1 genotype, HLA-DQA1 high and low expression by Nanostring, and clinical response (PR, SD, PD). Patients with HLA-DQAl*01 genotype are enriched for clinical response and are HLA-DQAlhlghas depicted in FIG 5C. Patients with HLA-DQB 1*05 or HLA-DQB 1*06 genotype are enriched for clinical response and are HLA- DQB lhlghas depicted in FIG 5C.

[0191] Table 3E shows clinical response rates of pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab by RECIST version 1.1 (PR or CR) grouped by HLA-DQAl*01 and not HLA-DQAl*01. Confirmed clinical response rates for all patients with known HLA-DQA1 alleles was 31%. Patients with at least 1 HLA-DQAl*01 allele had a 41% response rate, while patients no HLA-DQAl*01 allele had a 7.7% response rate. An analysis of patients with at least one HLA-DQB 1*05 or HLA-DQB 1*06 allele vs the absence of HLA-DQB 1*05 and HLA-DQB 1*06 alleles show identical clinical response rates to the HLA-DQA1 genotype analysis described above.

[0192] Median progression free survival was assessed per RECIST version 1.1.

[0193] Pancreatic cancer patients with HLA-DQAl*01 genotype demonstrated an increased median progression free survival following treatment with chemotherapy + TTX-030 + / - budigalimab as opposed to patients without HLA-DQAl*01 genotype as depicted in FIGs.5E-J and Table 3B and Table 3C. Median PFS in patients receiving chemotherapy + TTX-030 was 9.4 months for HLA-DQAl*01 patients versus 4.5 months for Not HLA- DQAl*01 (FIG. 5E). Median PFS in patients receiving chemotherapy + TTX-030 + budigalimab was 7.0 months for HLA-DQAl*01 patients versus 5.4 months for not HLA- DQAl*01 (FIG. 5F). Combined analysis of patients receiving chemotherapy + TTX-030 + / -424930-8149-5134.1Atty. Dkt. No. 144265-0107 budigalimab demonstrated that median PFS was 9.4 months for HLA-DQA1*O1 versus 5.5 months for Not HLA-DQ Al *01 (FIG. 5G).

[0194] In FIG. 5E, FIG. 5F, FIG. 5G, Table 3A, and Table 3B, these are a subset of patients with both Nanostring results and HLA genotyping results (n=29). When evaluating clinical outcome in these 29 patients, the 20 PDAC patients with at least 1 HLA-DQAl*01 allele have a median PFS RECIST of 9.4 months compared to a median PFS of 5.5 months for patients who have no HLA-DQAl*01 allele. Whether analyzing this 29-patient subset by HLA-DQ high vs low status or the presence of at least 1 HLA-DQBl*05 or HLA-DQB1*O6 allele vs the absence of HLA-DQBl*05 and HLA-DQB1*O6 alleles, there is no difference in the clinical outcome as measured by median PFS RECIST.

[0195] In FIG. 5H, FIG. 51, FIG. 5J, and Table 3C, there are 42 PDAC patients with HLA class II genotyping results. When evaluating clinical outcomes in these patients, there are 29 PDAC patients with at least 1 HLA-DQAl*01 allele who have a median PFS RECIST of 7.5 months compared to a median PFS of 5.5 months for 13 patients who have no HLA- DQA1 *01 allele. In analyzing these 42 patients for the presence or absence of at least 1 HLA- DQB 1 *05 or HLA-DQB 1 *06 allele, there is no difference in the clinical outcome as measured by median PFS RECIST.

[0196] In FIG. 5E, FIG. 5F, FIG. 5G, and Table 3D, there are 29 PDAC patients who have both Nanostring results and HLA class II typing results. In FIG. 5H, FIG. 51, FIG. 5J, and Table 3C, there are 42 PDAC patients with HLA class II genotyping results: 29 / 42 patients have corresponding Nanostring data while 13 / 42 patients have no Nanostring data. Whether looking at HLA-DQ status by Nanostring (HLA-DQA1 high vs low) or HLA class II genotypes (either a) HLA-DQ Al *01 vs not HLA-DQ Al *01 or b) HLA-DQB 1*05 or HLA-DQB 1*06 vs not HLA-DQB 1*05 and HLA-DQB 1*06), there are a subset of patients (who are either a) HLA-DQhlgh, b) have at least 1 HLA-DQ Al *01 allele, or c) have at least 1 HLA-DQB 1*05 or *06 allele) treated with TTX-030 + / - budigalimab + G / nP ), who have improved clinical benefit as measured by ORR or median PFS RECIST.

[0197] Table 3D shows an analysis of patients with both NanoString and HLA class II genotyping show consistent results. Table 3E shows clinical responders in pancreatic cohorts are HLA-DQAl*01.434930-8149-5134.1Atty. Dkt. No. 144265-0107444930-8149-5134.1454930-8149-5134.1464930-8149-5134.1Atty. Dkt. No. 144265-0107Table 4Example 7: RT-qPCR can distinguish HLA-DQhigh and HLA-DQlow patients similar to NanoString.

[0200] Fresh and / or archival tumor biopsy tissue are submitted as fixed formalin, paraffin embedded (FFPE) blocks or FFPE slides. Biopsies are collected and processed per institutional guidelines and procedures for the procurement of fresh tumor biopsy samples. Archival tissue collected within ninety (90) days prior to first dose is acceptable if there has been no intervening therapy.

[0201] RNA is extracted from FFPE tissue slides using MagMAX FFPE DNA / RNA Ultra Kit (ThermoFisher, Waltham, MA) according to the manufacturer's protocols. Paraffin is removed from the slides and tissue is digested with protease. RNA is manually isolated from the digested tissue using magnetic beads and centrifugation and purified RNA is collected following DNase treatment.

[0202] Quantitative Reverse Transcription polymerase chain reaction (RT-qPCR or qPCR) is a method to measure gene expression such as HLA-DQA1 or HLA-DQB1. First, RNA is converted into complimentary DNA (cDNA) by reverse transcriptase. During reverse transcription, a mix of random oligonucleotides is used to initiate first strand synthesis of all RNA species including mRNA and rRNA. The resulting cDNA is used for a qPCR.

[0203] Gene-specific RT-qPCR probes are made using published sequences (such as Zajacova, et al, 2018) to measure total HLA-DQA1 or HLA-DQB1 gene expression by a quantitative polymerase chain reaction (qPCR).

[0204] RT-qPCR probes are gene-specific, dual-labeled (fluorophore and quencher) oligonucleotides that anneal to a complimentary target sequence. An intact RT-qPCR probe’s fluorescence is inhibited by its quencher’s proximity to its fluorophore. At the elongation step of each PCR cycle, the 5 ’-3’ exonuclease activity of Taq polymerase cleaves hybridized RT- qPCR probes, resulting in the separation of fluorophore and quencher. No longer quenched, the fluorophore emits a fluorescent signal. Fluorescence is measured after each cycle and the intensity of the fluorescent signal reflects the momentary amount of DNA amplicons in the sample at that specific time.

[0205] Gene expression of tumor tissues by qPCR is analyzed using an ABI7500 Taqman (ThermoFisher) or Rotor Gene Q (Qiagen).474930-8149-5134.1Atty. Dkt. No. 144265-0107Example 8: IHC to establish expression of HLA-DQA1 or HLA-DQB1 and correlation of clinical responses in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab.

[0206] Biopsies are collected and processed per institutional guidelines and procedures for the procurement of fresh tumor biopsy samples. Archival tissue collected within ninety (90) days prior to first dose is acceptable if there has been no intervening therapy. Fresh and / or archival tumor biopsy tissues are submitted as fixed formalin, paraffin embedded (FFPE) blocks, or unstained FFPE slides.

[0207] Immunohistochemistry (IHC) is a method for demonstrating the presence and location of proteins in tissue sections using a colorimetric readout. FFPE tissue sections of 4- 5 micron thickness may be mounted on unstained slides. Prior to IHC staining, unstained slides may be deparaffinized and rehydrated and then antigen retrieval may be performed to expose antigenic sites to allow antibodies to bind. For IHC staining, a primary antibody that recognizes HLA-DQA1 and / or HLA-DQB1 is allowed to bind to the tissue. If the primary antibody is conjugated to an enzyme such as peroxidase or alkaline phosphatase, a secondary enzyme is not needed. If a secondary antibody is needed, a secondary antibody conjugated to an enzyme is added to detect primary antibody binding to tissue. Whether detection is direct or indirect, a substrate is added, which produces a colored product that stains the tissue where HLA-DQA1 or HLA-DQB1 is expressed. The stained slides or an image of the stained slides may be analyzed by a pathologist to provide a quantitative and / or qualitative assessment of protein expression by the colorimetric staining. It may be possible to develop an automated program to quantitate protein expression by IHC.

[0208] A schematic illustration of IHC is set forth in FIG. 7 showing the colored product, peroxidase or alkaline phosphatase, substrate, secondary antibody, primary antibody, proteins, and fixed cell tissue.Example 9: RNA biomarkers to establish expression of HLA-DQA1 or HLA-DQB1 and correlation of clinical responses in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab.

[0209] Biopsies may be collected as above. RNA biomarkers may be isolated as follows See, for example, Cabus, L., Lagarde, J., Curado, J. et al. Current challenges and best practices for cell-free long RNA biomarker discovery. Biomark Res 10, 62 (2022), which is incorporated by reference herein in its entirety, including any drawings). Blood can be obtained from patients and centrifuged to get plasma or serum. To reduce RNA contamination from484930-8149-5134.1Atty. Dkt. No. 144265-0107 blood cells, the most common approach is to use serum (the fraction of blood remaining after the blood clotting) or plasma (the acellular fraction of the blood) instead of whole blood.

[0210] Whether using plasma or serum, a common limitation is the release of RNAs derived from red blood cells (RBC) and / or platelets during sample processing. During blood clotting, a necessary step for serum isolation, RNAs are released from blood cells and platelets, affecting the circulating RNA spectrum. However, to separate plasma from other blood components, blood cells and platelets have to be removed with several centrifugation steps. An incorrect centrifugation or handling of the samples could result in cellular contamination. Hemolysis controls are a common assessment to quantify the presence of RBC RNA and measure contamination by cellular lysis.

[0211] After isolation of the nucleic acids and before further processing, a step of DNAse digestion is required to limit the contamination of the sample with co-purified DNA. A final step of RNA quantification is required before moving forward to library preparation. The cfRNA obtained from a blood sample represents an approximation to a snapshot of the transcriptome of the individual.

[0212] The most common strategy for RNA isolation from biofluids is based on RNA extraction kits designed and optimized for plasma and / or serum. Commercial column-based kits are more commonly used than traditional guanidium-thiocyanate or phenol-chloroform methods. One major concern regarding RNA isolation from plasma is DNA contamination. The majority of cfRNA isolation kits recover a fraction of the cfDNA present in the biofluid. During library preparation, DNA contamination is amplified along with RNA affecting the results. To minimize this bias, the most common strategy is the incorporation of an additional step where the samples are treated with DNAse. This can be done before the extraction (on- column) or after.

[0213] In order to limit the effect of other technical biases associated with RNA isolation, the addition of exogenous RNAs as controls to compare the efficiency of the RNA extraction can be used. Prior to processing of plasma / serum, it is recommended to add external RNA molecules to act as proxies for correct RNA isolation. Spike-ins are exogenous RNAs with similar GC content to endogenous RNAs with sequences not found in the human genome. They are added to the samples prior to RNA isolation in a known concentration and their detection is useful to assess biases introduced during RNA isolation. Spike-ins have been successfully used to compare RNA profiles across biofluids, allowing absolute quantification and revealing a 10,000 fold difference in concentration.494930-8149-5134.1Atty. Dkt. No. 144265-0107

[0214] Library preparation and sequencing are performed according to methods known the in the art. Approximately 80% of the cellular RNA is ribosomal RNA (rRNA) and this number is even bigger in cfRNA, with more than 90% of the RNA found in the circulation belonging to this type of RNA. In order to remove high concentrations of rRNA, there are two methods: polyA enrichment or rRNA depletion.

[0215] During library preparation, another step leading to the introduction of biases is adaptor ligation and PCR amplification. Due to secondary structures and enzyme affinity, some sequences are more prone to ligate to adaptor sequences and amplify than others. In order to reduce this bias, many protocols have incorporated the use of Unique Molecular Identifiers (UMIs) in the early stages of library preparation. UMIs are random sequences of 4-10 nt that are ligated to the DNA / RNA molecules before PCR amplification. The use of UMIs allows the identification of PCR-duplicated reads that originate from the same initial molecule, and the in silico correction of this clonal amplification. Additionally, if the UMIs are incorporated before adaptor ligation, they can also help minimize adaptor ligation biases.

[0216] Following the same rationale used to evaluate biases during RNA isolation, spike-ins are also useful in measuring technical variability introduced during library preparation. Similar to the spike-ins used to assess RNA isolation, they are added at a known concentration to correct for the amplification bias during library preparation and can be useful to quantify and normalize in silico the sequencing output.

[0217] Once libraries are prepared and quantified, the next step is to sequence them. Often, batch effects are observed when samples used in the same study are sequenced in different rounds. Commercially available control libraries can be added at known concentrations to measure the reproducibility of sequencing and later used to mitigate batch effects. The most common example is the PhiX Control Libraries generated from the PhiX virus.

[0218] These spike-in libraries have two functions. First, they act as positive controls of the sequencing run, ensuring clustering reaction and generating a number of clusters depending on the quantity of the spike-in added. And second, they act as a technical control for sequencing accuracy, aligning the sequences to the reference genome of the spike-in library.

[0219] After the initial quality control of the sample, the data is processed. One of the most prevalent issues with the processing of raw RNA-seq data is normalization. It consists in correcting in silico for technical biases that could mask biological information. RNA-seq is the most used tool to measure gene expression, although unlike other methods like RT-qPCR,504930-8149-5134.1Atty. Dkt. No. 144265-0107 it does not allow for absolute quantification. A normalization based on spike-in controls, added at the library preparation step, is one of the methods used to achieve absolute quantification of the transcriptome in cellular RNA (See Bayega A, Oikonomopoulos S, Gregoriou ME, Tsoumani KT, Giakountis A, Wang YC, et al. Nanopore long-read RNA-seq and absolute quantification delineate transcription dynamics in early embryo development of an insect pest. Sci Rep. 2021; 11(1):7878., which is incorporated by reference herein). This method is also shown to be highly reproducible in plasma samples.

[0220] Once the raw data is processed, the identification of potential biomarkers can follow two different routes: comparative analysis of cfRNA profiles and machine learning (ML) methods. Both methods are useful in obtaining signatures of high value for diagnosis and prognosis.Example 10: Phase 2 Inclusion and Exclusion and Dose Identification of Anti human CD39 Antibody in Combination with Chemotherapy with or without Anti human PD-1 antibody in Subjects with Locally Advanced Unresectable or Metastatic Pancreatic Cancer

[0221] Inclusion criteria included male or female subjects >18 years of age at the time of screening (or for South Korea: >19 years of age at the time of screening), subject must weigh >35 kg, evidence of measurable disease as assessed by the investigator per RECIST version 1.1, subject must be appropriate for treatment with nab-paclitaxel and gemcitabine chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0222] Further inclusion criteria included the availability of tumor tissue (obtained by biopsy during Screening, or archival if collected within 90 days prior to the first dose of study drug and in the absence of intervening therapy). Biopsy of the primary site of disease in the pancreas or intrathoracic biopsies should not be performed to obtain tumor tissue for the purpose of this study. Subjects with contraindications for a biopsy procedure and without acceptable archival tissue samples are not eligible.

[0223] Inclusion criteria also included required baseline laboratory tests, defined as: a. Hematology: absolute neutrophil count (ANC) >1.2 k / pL, platelets >100 k / pL, hemoglobin (Hgb) >9 g / dL. b. Coagulation: prothrombin time (PT) and International Normalized Ratio (INR) <1.2 x upper limit of normal (ULN), except for subjects receiving anticoagulation; subjects must be on a stable dose of warfarin for 6 weeks prior to enrollment.514930-8149-5134.1Atty. Dkt. No. 144265-0107 c. Kidney: Creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) >40 mL / min calculated by Cockcroft-Gault or CKD-EPI. d. Liver: AST and ALT <2.5 x ULN (or <5 x ULN with hepatic metastases); total bilirubin <2 x ULN (or <3 x ULN with Gilbert’s syndrome); serum albumin >3.0 g / dL.

[0224] Resolution of adverse effects from any prior chemotherapy, immunotherapy, or prior systemic anticancer therapy, radiotherapy, or surgery to Grade 1 or baseline (except Grade 2 alopecia and Grade 2 sensory neuropathy) were also required.

[0225] Inclusion criteria also included the requirement for histologically or cytologically confirmed diagnosis of locally advanced, unresectable or metastatic pancreatic adenocarcinoma. No prior systemic treatment for metastatic disease. Prior neoadjuvant or adjuvant systemic chemotherapy is permitted in the absence of disease progression within 6 months following last dose of chemotherapy. No prior treatment with therapeutics specifically targeted to enhancing or de-repressing anti-tumor immunity including but not limited to checkpoint inhibitors or agents targeting the adenosine pathway (CD39, CD73 or adenosine receptor inhibitors).

[0226] Women of childbearing potential and all men must agree to use 2 highly effective methods of contraception through 6 months (180 days) after the last administration of any study treatment. Highly effective contraception methods include total abstinence; female sterilization (tubal ligation, bilateral oophorectomy, and / or hysterectomy); male sterilization (at least 6 months prior to Screening); intrauterine device or intrauterine hormone-releasing system; oral, injected, or implanted hormonal contraception with only progestogen at least 30 days before first dose; AND barrier methods of contraception; oral, injectable, transdermal, or intravaginal combined hormonal contraception with estrogen and progestogen at least 30 days before first dose (Prescribing information should be followed if different from the above).

[0227] Subjects with history of congestive heart failure must have cardiac echocardiogram (ECHO) or multigated acquisition (MUGA) scan indicating left ventricular ejection fraction >45% within 28 days prior to the first dose of study treatment.

[0228] Exclusion criteria included subjects with a history of clinically significant allergy or hypersensitivity to planned study treatment components or to any monoclonal antibody (defined as any Grade 3 reaction lasting >48 hours despite optimal therapy). Subjects were also excluded if they had a history of SJS, Toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS).524930-8149-5134.1Atty. Dkt. No. 144265-0107

[0229] A history of autoimmune disease including but not limited to rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, non-infectious pneumonitis, interstitial lung disease (ILD), requiring systemic treatment that required systemic steroids or immunosuppressive agents within the last 2 years resulted in subject exclusion. Subjects with findings consistent with active autoimmune disease on Screening evaluation (computed tomography [CT] showing pneumonitis or ILD, physical examination findings) are not eligible. NOTE: History of vitiligo, autoimmune thyroiditis, or mild psoriasis are allowed.

[0230] Subjects with any active disease requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to Day 1 of treatment were excluded from the study. Inhaled, intranasal, intra-articular and topical [including ocular] steroids are allowed. Adrenal replacement [i.e., physiologic replacement] doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease).

[0231] Subjects with a history of primary immunodeficiency, bone marrow transplantation, chronic lymphocytic leukemia, solid organ transplantation, or previous clinical diagnosis of tuberculosis were excluded from the study. Use of investigational agent within 14 days prior to the first dose of study drug resulted in study exclusion. Subjects with evidence of active central nervous system (CNS) metastatic disease or carcinomatous meningitis were excluded from the study. Subjects with a known history of human immunodeficiency virus (HIV) or other chronic immunodeficiency were excluded from the study.

[0232] Women who are pregnant or breastfeeding were excluded from the study.

[0233] If the subject had received live vaccine within 28 days prior to the first dose of study drug, then they were excluded from the study.

[0234] It the subject has had major surgery per the Investigator within 28 days prior to the first dose of study drug, and the surgical wound is not adequately healed, then they were excluded from the study. A diagnostic or research biopsy does not exclude subjects from enrollment. Placement of a vascular access device such as a Port-A-Cath is not considered major surgery.

[0235] A subject was excluded from the study if they had an uncontrolled intercurrent illness including, but not limited to:• Uncontrolled diabetes• New York Heart Association (NYHA) Class 3 or 4 congestive heart failure534930-8149-5134.1Atty. Dkt. No. 144265-0107• Unstable angina, arrhythmia, or myocardial infarction within 6 months prior to Screening• Poorly controlled hypertension, defined as a blood pressure consistently above 160 / 90 mmHg despite optimal medical management• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX®) are allowed• Active or chronic viral hepatitis B or C infection• Uncontrolled thyroid disease• Active infection requiring systemic therapy; subjects receiving ongoing systemic antibiotic, antiviral or antifungal therapy for maintenance should be discussed with the medical monitor prior to Screening and enrollment.

[0236] A subject with a history of any other malignancy within the past 3 years except for: curatively treated carcinoma in situ; localized nonmelanoma or early-stage melanoma skin cancer; or Stage 1 uterine cancer or localized prostate cancer that is considered adequately treated by the Investigator were excluded from the study. Subjects with hematologic malignancies and anticipated OS of >5 years may be considered for enrollment but should be discussed with the Medical Monitor prior to evaluation.Table 5

[0237] Patient demographics for each treatment (i.e., Gem / NP (e.g., chemotherapy) + anti-human CD39 antibody ± budigalimab, or Gem / NP alone) were relatively balanced across age, sex, and race (Table 5). For example, median age ranged from 63.5 - 68.0 years across the544930-8149-5134.1Atty. Dkt. No. 144265-0107 three treatment groups. Male patient percentages ranged from 55%-60.3% across the three treatment groups. Correspondingly, female patient percentages ranged from 39.7% - 45% across the three treatment groups. Patient racial demographics consisted of Caucasian (43.3%- 54.4%), Black or African American (2.9%-3.3%), Asian (26.5%-30%), and unknown (13.2%- 23.3%) across the three treatment groups. Further, median body weight ranged from 62.6 kg- 67.0 kg and median body mass index (BMI) ranged from 22.99 - 24.6 across the three treatment groups.

[0238] Patient key baseline characteristics are similar for each treatment (i.e., Gem / NP + anti-human CD39 antibody ± budigalimab, or Gem / NP alone) (Table 6). For example, 41.2%-50% of patients were characterized as having an Eastern Cooperative Oncology Group (ECOG) scale of 0 across the three treatment groups. Correspondingly, 50%-58.8% of patients were characterized as having an ECOC scale of >1 across the three treatment groups. 69.7%- 78.3% of patients demonstrated presence of liver metastasis across the three treatment groups. Eligible patients must have had no prior treatment for metastatic disease. Further, 8%-12% of patients had received prior lines of treatment before administration of the study treatment regimens.Table 6

[0239] Two study treatment regimens were evaluated in study participants with pancreatic adenocarcinoma:3. Gem / NP + anti-human CD39 antibody (“doublet”)4. Gem / NP + anti-human CD39 antibody + budigalimab (“triplet”)Gemcitabine (1000 mg / m2) / nab-paclitaxel (125 mg / m2) (i.e., G / NP) was administered on Days 1,8, and 15 of each 28-day treatment cycle according to standard clinical practice.554930-8149-5134.1Atty. Dkt. No. 144265-0107

[0240] The anti-human CD39 antibody (i.e., TTX-030) was administered intravenously at 40 mg / kg over at least 60 minutes on Day -7 (loading dose), and then at 20 mg / kg before the administration of chemotherapy on Days 1 and 15 of each 28-day treatment cycle.

[0241] The budigalimab (i.e., the anti-human PD-1) antibody was administered intravenously at 500 mg over at least 60 minutes on Day 1 of each 28-day treatment cycle after the administration of the anti-human CD39 antibody and before the administration of chemotherapy.Example 11: Phase 2 Overall Response Rate, Progression-Free Survival, and Overall Survival in Pancreatic Cancer Patients Treated with Chemotherapy + TTX-030 ± Budigalimab

[0242] Overall response rate (ORR), median overall survival (mOS), and median progression-free survival (mPFS) were assessed per RECIST version 1.1 (Tables 9-12).

[0243] The efficacy analysis was based on the efficacy-evaluable population of study participants and the documented investigator-assessed tumor response according to published and internationally accepted guidelines. Overall response rate (ORR), median overall survival (mOS), median progression-free survival (mPFS), and were assessed per RECIST version 1.1 (Tables 8 and 9).• The overall response rate (ORR) was defined as the sum of the confirmed partial responses (PRs) and complete responses (CRs) divided by the number of efficacy- evaluable study participants.• The progression-free survival (PFS) is defined as the time from the date of initiation of study treatment until the first assessment of progressive disease (PD). Censoring rules were applied as follows: o at the time of last evaluable tumor assessment in the absence of documented disease progression or death. o at the time of last evaluable tumor assessment if alternative anti -tumor therapy was started in the absence of documented disease progression.

[0244] Pancreatic cancer patients treated TTX-030 combination therapies (i.e., chemotherapy + TTX-030 ± budigalimab) showed improved ORR vs chemotherapy alone (FIG. 8 and Table 7). For example, chemotherapy alone resulted in 19% confirmed ORR, while chemotherapy + TTX-030 resulted in 24% confirmed ORR and chemotherapy + TTX-030 +564930-8149-5134.1Atty. Dkt. No. 144265-0107 budigalimab resulted in 32% ORR. Unconfirmed ORR ranged from 31%-37%, with chemotherapy resulting in the lowest unconfirmed ORR percentage.Table 7

[0245] Improved mPFS were observed in pancreatic cancer patients treated with chemotherapy + TTX-030 + budigalimab (FIG. 9 and Table 8). The number of PFS events ranged from 52%-65% across the three treatments; however, patients treated with chemotherapy + TTX-030 + budigalimab demonstrated an mPFS of 7.3 months. Patients treated with chemotherapy + TTX-030 or chemotherapy alone demonstrated an mPFS of 5.4 months or 5.6 months, respectively (Table 8). Interestingly, mPFS were improved in patients with liver metastases after treatment with chemotherapy + TTX-030 + budigalimab relative to other regimens (FIG. 10 and Table 9). For example, liver metastasis patients treated with treated with chemotherapy + TTX-030 + budigalimab demonstrated an mPFS of 7.3 months, while patents treated with chemotherapy + TTX-030 or chemotherapy alone demonstrated an mPFS of 4.5 months or 4.3 months, respectively (Table 9). This result was surprising because Anti- PD1 antibodies (e.g., budigalimab) typically have less benefit for patients with liver metastases.Table 9574930-8149-5134.1Atty. Dkt. No. 144265-0107

[0246] Pancreatic cancer patients demonstrated consistent ORR and mPFS results across Phase 1 and Phase 2 studies following treatment with chemotherapy + TTX-030 ± budigalimab (Table 10). Phase 1 trial patients treated with chemotherapy + TTX-030 demonstrated an mOS of 15.5 months, while patients treated with chemotherapy + TTX-030 + budigalimab demonstrated an mOS 21.9 months. Patients treated with chemotherapy + TTX- 030 demonstrated an ORR of 27% and 24% for the Phase 1 and Phase 2 studies, respectively. Patients treated with chemotherapy + TTX-030 + budigalimab demonstrated an ORR of 33% and 32% for the Phase 1 and Phase 2 studies, respectively. Patients treated with chemotherapy + TTX-030 demonstrated an mPFS of 5.8 months and 5.4 months for the Phase 1 and Phase 2 studies, respectively. The mPFS for patients treated with chemotherapy + TTX-030 + budigalimab was 7.7 months and 7.3 months for the Phase 1 and Phase 2 studies, respectively.Table 10

[0247] Further, pancreatic cancer patients demonstrated a median overall survival (mOS) of 33% following treatment with chemotherapy + TTX-030 + budigalimab, a median overall survival of 36% following treatment with chemotherapy + TTX-030, and a median overall survival of 40% following treatment with chemotherapy alone (Table 11). Median times for patient follow-up after treatments with chemotherapy + TTX-030 ± budigalimab was 7 months, while follow-up after chemotherapy alone was 9 months. It was noted that proportionally fewer mOS events for chemotherapy + TTX-030 ± budigalimab treatments were observed related to chemotherapy alone. mOS events are projected to increase to at least 50% as study progresses.584930-8149-5134.1Atty. Dkt. No. 144265-0107Table 11Example 12: Phase 2 Adverse Effects in Pancreatic Cancer Patients Treated with Chemotherapy + TTX-030 ± Budigalimab Baseline expression of HLA-DQB1 is correlated with increased clinical responses in pancreatic cancer patients treated with chemotherapy + TTX-030 + / - budigalimab

[0248] Treatment-emergent adverse events (TEAE) were monitored in pancreatic cancer patients following treatment with chemotherapy + TTX-030 ± budigalimab, or chemotherapy alone (Table 12). Treatment-emergent adverse events refer to an adverse event (AE) that specifically emerges or worsens after the administration of a study product or treatment. The severity of an adverse event was divided into 5 distinct groups:• Grade 1 : Mild - Asymptomatic or mild symptoms; intervention is not required.• Grade 2: Moderate - Minimal intervention is needed, and the event limits instrumental activities of daily living (ADL).• Grade 3 : Severe - Medically significant but not immediately life-threatening; may require hospitalization or significantly limits self-care ADL.• Grade 4: Life-threatening - Urgent intervention is required due to life-threatening consequences.• Grade 5: Death - The adverse event results in death.594930-8149-5134.1Atty. Dkt. No. 144265-0107Table 12

[0249] For example, patients with any form of TEAE ranged from 98.4%-100% across all three treatment groups. It was noted that pancreatic cancer patients treated with chemotherapy + TTX-030 ± budigalimab demonstrated a slight increase in the frequency of Grade >3 TEAE relative to patients treated with chemotherapy alone (Table 13). Discontinuation for each treatment due to AEs was 3% for chemotherapy + TTX-030, 8% for chemotherapy + TTX-030 ± budigalimab, and 5% for chemotherapy alone.604930-8149-5134.1Atty. Dkt. No. 144265-0107Table 13614930-8149-5134.1Atty. Dkt. No. 144265-0107

[0250] The terms “a,” “an,” “the” and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0251] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of’ excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0252] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.Table S Sequences.624930-8149-5134.1Atty. Dkt. No. 144265-0107634930-8149-5134.1Atty. Dkt. No. 144265-0107644930-8149-5134.1Atty. Dkt. No. 144265-0107654930-8149-5134.1Atty. Dkt. No. 144265-0107664930-8149-5134.1Atty. Dkt. No. 144265-0107674930-8149-5134.1Atty. Dkt. No. 144265-0107684930-8149-5134.1Atty. Dkt. No. 144265-0107694930-8149-5134.1Atty. Dkt. No. 144265-0107704930-8149-5134.1Atty. Dkt. No. 144265-0107Equivalents

[0253] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. The subject matter of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and / or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and / or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.714930-8149-5134.1

Claims

Atty. Dkt. No. 144265-0107WHAT IS CLAIMED IS:

1. A method of treating a pancreatic cancer, the method comprising administering a therapeutically effective amount of an anti-CD39 antibody in combination with a chemotherapy, and optionally a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-Ll antibody, to a human subject having a pancreatic cancer, the anti-CD39 antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID: 75 and light chains each consisting of the amino acid sequence of SEQ ID NO: 76.

2. The method according to claim 1, wherein the chemotherapy comprises one or more of gemcitabine and nab-paclitaxel.

3. The method according to any one of claims 1 or 2, comprising administering the anti- CD39 antibody in combination with the chemotherapy and the anti-PD-1 antibody or anti-PD- Ll antibody.

4. The method according to any one of claims 1-3, wherein the anti-CD39 antibody is administered to the human subject intravenously at 40 mg / kg over at least 60 minutes once and then at 20mg / kg administered every two weeks during 28-day treatment cycles.

5. The method according to any one of claims 1-4, wherein the anti-PD-1 antibody is administered intravenously at 500 mg over at least 60 minutes on day 1 of each 28-day treatment cycle after the administration of the anti -human CD39 antibody and before the administration of chemotherapy.

6. The method according to any one of claims 1-5, wherein the chemotherapy comprises gemcitabine administered at a dosage of about 1000 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.

7. The method according to any one of claims 1-6, wherein the chemotherapy comprises nab-paclitaxel administered at a dosage of about 125 mg / m2on days 1, 8, and 15 of each 28-day treatment cycle.724930-8149-5134.1Atty. Dkt. No. 144265-01078. The method according to any one of claims 1-7, wherein the anti-PD-1 antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NOS: 77 or 78, and light chains each consisting of the amino acid sequence of SEQ ID NO: 79,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 80 and light chains each consisting of the amino acid sequence of SEQ ID NO: 81, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 82 and light chains each consisting of the amino acid sequence of SEQ ID NO: 83.

9. The method according to claim 8, wherein the anti-PD-1 antibody consists of an antibody consisting of heavy chains each consisting of the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78 and light chains each consisting of the amino acid sequence of SEQ ID NO: 79.

10. The method according to claim 1, wherein the anti-PD-Ll antibody is selected from the following:(a) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 84 and light chains each consisting of the amino acid sequence of SEQ ID NO: 85,(b) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 86 and light chains each consisting of the amino acid sequence of SEQ ID NO: 87, or(c) heavy chains each consisting of the amino acid sequence of SEQ ID NO: 88 and light chains each consisting of the amino acid sequence of SEQ ID NO: 89.

11. The method according to any one of claims 1-10, wherein the subject achieves a median duration of response (DoR) of at least 2 months as compared to standard of care therapies.

12. The method according to any one of claims 1-11, wherein the subject achieves progression free survival (PFS) of at least 2 months as compared to standard of care therapies.

13. The method according to any one of claims 1-12, wherein the subject achieves an overall survival (OS) of at least 2 months as compared to standard of care therapies.734930-8149-5134.1Atty. Dkt. No. 144265-010714. The method according to any one of claims 1-13, wherein the subject exhibits stable disease (SD); partial response (PR); or complete response (CR) per RECIST version 1.1.

15. The method according to any one of claims 1-14, where the pancreatic cancer comprises locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer.744930-8149-5134.1

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