Efficacy predictive biomarkers for anti-SIRPA antibodies

Abstract

This application relates generally to the treatment of cancer in patients who exhibit immune cells, particularly myeloid cells, such as tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs, and / or tumor-associated neutrophils, expressing the biomarkers CD11b and SIRPα within the tumor microenvironment. These patients have been identified as most likely to respond to therapy involving the administration of anti-SIRPα antagonist antibodies.

Description

[Technical Field]

[0001] This application generally relates to the treatment of patients with cancer by using anti-SIRPα antibodies or antigen-binding fragments thereof. In particular, the present invention relates to uses and methods of using anti-SIRPα antagonist antibodies or antigen-binding fragments thereof to treat patients who are likely to respond positively to treatment for cancer by administering the anti-SIRPα antibody or antigen-binding fragment thereof alone or in combination with another therapeutic compound (e.g., another antibody) or treatment method (e.g., radiation therapy or chemotherapy) or so-called standard therapy (i.e., therapy normally recommended to treat the cancer occurring in the patient).

[0002] Accordingly, this application relates to the treatment of cancer in patients who exhibit immune cells, particularly myeloid cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly myeloid-derived suppressor cells (MDSCs), that express the biomarkers CD11b and SIRPα in the tumor microenvironment. These patients have been identified by the present invention as most likely to respond to therapy involving the administration of anti-SIRPα antagonist antibodies. The present invention is particularly dedicated to the measurement of these specific markers expressed by immune cells, particularly myeloid cells, e.g., tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, obtained from patients with cancer, and the administration of anti-SIRPα antibodies or antigen-binding fragments thereof, alone or in combination, to patients whose cells express the specific markers. [Background technology]

[0003] Cancer is a major health problem worldwide, resulting in approximately 9.5 million deaths per year and more than 20 million people developing cancer annually (World Health Organization Global Cancer Report, 2018). Targeting immune checkpoints in adaptive immunity has shown great therapeutic efficacy for combating many cancers. Immune checkpoints in myeloid cells, such as macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and polymorphonuclear leukocytes or neutrophils (PMNs), remain understudied, yet these cells represent abundant immune cell types in many solid tumors and are often associated with poor outcomes. Signal regulatory protein alpha (SIRPα, SIRP-alpha, SIRPα, also known as CD172a or SHPS-1) is expressed in monocytes, most subpopulations of tissue macrophages, MDSCs, granulocytes, subsets of DCs in lymphoid tissues, some myeloid progenitor cells, and neurons at various levels, with prominent expression in synapse-rich regions of the brain, such as the granular layer of the cerebellum and hippocampus.

[0004] SIRPα is the prototypic member of the SIRP-paired receptor family of closely related SIRP proteins, which includes SIRPα, SIRPg (also known as SIRP-gamma, SIRPγ, CD172g, or SIRP beta-2), and SIRPb (also known as SIRP-beta, SIRPβ, or CD172b). Signal-regulatory proteins (SIRPs) constitute a family of cell-surface glycoproteins expressed in myeloid (including macrophages, granulocytes, myeloid dendritic cells, and mast cells) and neural cells (reviewed in Barclay, AN, and Brown, MH, Nat Rev Immunol 6, 457-64 (2006); see also WO97 / 48723), as well as some normal tissue and tumor cells. CD47, a ubiquitously expressed transmembrane glycoprotein, functions as a cell-associated ligand for SIRPα, binding to the NH2-terminal extracellular terminus of SIRPα. The role of SIRPα is best documented for its inhibitory role in phagocytosis of host cells by macrophages. In particular, binding of SIRPα on macrophages by CD47 expressed on target cells generates an inhibitory signal that negatively regulates phagocytosis. However, more recent findings also demonstrate additional positive signaling effects mediated by SIRPα binding (Shultz, LD et al. (1995) J Immunol 154, 180-91).

[0005] When expressed by myeloid cells, SIRPα interacts with the ubiquitous receptor CD47, a key immune checkpoint of the innate response involved in regulating myeloid function. The interaction between SIRPα and CD47 provides a downregulatory signal that inhibits host cell phagocytosis. Because CD47 is widely overexpressed on some cancer cells, CD47 functions as a "don't eat me" signal in some tumors, thereby evading phagocytosis. The potential contribution of CD47-SIRPα interaction in cancer cell clearance has been intensively investigated in recent years. Tumor abundance of CD47 receptors has been shown to be inversely correlated with overall patient survival and constitutes an unfavorable prognostic factor for several cancer types.

[0006] Therefore, the SIRPα / CD47 pathway has been the target of various drug development efforts to enhance macrophage phagocytosis. These include the use of fragmented / truncated SIRPα and / or CD47 proteins and antibodies against them. When cancer cells overexpress CD47, they become resistant to macrophage invasion, even when coated with therapeutic antibodies. Blockade of the SIRPα / CD47 pathway with CD47-targeting drugs has been shown to enhance antibody-dependent phagocytosis by macrophages. These treatments have also been shown to synergize with depleting therapeutic anti-cancer antibodies, such as trastuzumab (anti-Her2), cetuximab (anti-EGFR), rituximab (anti-CD20), and alemtuzumab (anti-CD52).

[0007] Therefore, anti-human SIRPα antibodies capable of disrupting the binding between SIRPα and CD47 have been developed in recent years. Nevertheless, there is a need for improved uses of these antibodies, particularly for modulating their effects in vivo, for example, by improving patient response to anti-SIRPα antibodies or antigen-binding fragments thereof. There is also a need for improved uses of these compounds in combination with current treatments or current therapies.

[0008] In this regard, being able to reliably determine the likelihood of a given patient responding positively to a treatment, particularly in patients being treated for cancer, is of crucial importance to the patient. In particular, there is a need to assess whether a proposed treatment for a patient with cancer is adapted to effectively treat the disease. WO2014 / 186761 describes genetic biomarkers associated with responsiveness to anti-CD47 agents (and, notably, anti-SIRPα antibodies), and lists the genes SPP1, CHIT1, FCyR2A, and FCyR3A as putative markers of this responsiveness. WO2020 / 107115 describes biomarkers for CD47 tumor treatment. The identified markers are secreted proteins or cellular immune receptors (monocyte chemoattractant protein 3 (MCP-3), monocyte chemoattractant protein 1 (MCP-1), interleukin-1 alpha (IL-1A), interleukin-8 (IL-8), macrophage inflammatory protein 1-alpha (MIP-1α), macrophage inflammatory protein 1-beta (MIP-1β), MIG (Monokine Induced by Gamma Interferon). These biomarkers are not associated with the efficacy of cancer treatment. Moreover, the biomarkers described in the above-referenced applications do not refer to predictive biomarkers of efficacy. The biomarkers represent drug-target binding and their association with clinical response.

[0009] Usually, when searching for biomarkers for immunotherapy, those skilled in the art measure the expression of target molecules on tumors to estimate the potential efficacy of antibodies targeting this molecule.Therefore, since CD47 is a molecule expressed by tumor cells, those skilled in the art can measure the expression level of CD47 to evaluate whether the use of anti-SIRPα antibody may benefit patients who receive such antibody as treatment.The present inventors have shown that CD47 expression is highly heterogeneous in tumor cells.

[0010] Applicants have now shown that heterogeneous CD47 expression on tumor cells is observed in patients with advanced disease. Moreover, CD47 has different ligands that are also involved in tumorigenesis. Therefore, when treatment is based on the use of anti-SIRPα antibodies or antigen-binding fragments thereof, CD47 may not constitute a reliable predictive biomarker for cancer treatment in patients in need of treatment. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO97 / 48723 [Patent Document 2] WO2014 / 186761 [Patent Document 3] WO2020 / 107115 [Patent Document 4] WO2020 / 099653 [Patent Document 5] WO2019 / 023347 [Patent Document 6] WO2022 / 254379 [Patent Document 7] WO2020 / 068752 [Patent Document 8] WO2021 / 226576 [Patent Document 9] WO2021 / 226591 [Patent Document 10] WO2021174127 [Patent Document 11] WO2019 / 226973 [Patent Document 12] WO2018 / 190719 [Patent Document 13] U.S. Patent Application Publication No. 20210347908 [Patent Document 14] WO2020 / 102422 [Patent Document 15] WO0066159 [Patent Document 16] WO200140307 [Patent Document 17] WO2009131453 [Patent Document 18] WO2013056352 [Patent Document 19] WO2014149477 [Patent Document 20] WO2015138600 [Patent Document 21] WO2016063233 [Patent Document 22] WO2016205042 [Patent Document 23] WO2017178653 [Patent Document 24] WO2018008470 [Patent Document 25] WO2018026600 [Patent Document 26] WO2018057669 [Patent Document 27] WO2018107058 [Patent Document 28] WO2018141964 [Patent Document 29] WO2018160739 [Patent Document 30] WO2018210793 [Patent Document 31] WO2019183266 [Patent Document 32] WO2019200462 [License 33] WO2020006374 [Patent Document 34] WO2020013170 [License 35] WO2020033646 [License 36] WO2020180811 [License 37] WO2020247820 [License 38] WO2021022044 [License 39] WO2021032078 [License 40] WO2021076908 [License 41] WO2021129697 [Patent Document 42] WO2021185273 [License 43] CN111635458 [License 44] WO2021222746 [License 45] CN113735973 [License 46] CN111995682 [License 47] CN112010979 [License 48] CN112574310 [License 49] WO2014 / 194302 [License 50] WO2017 / 040790 [Patent Document 51] WO2017 / 19846 [Patent Document 52] WO2017 / 024465 [License 53] WO2017 / 025016 [Patent Document 54] WO2017 / 132825 [Patent Document 55] WO2017 / 133540 [Patent Document 56] WO2006 / 121168 [Non-patent literature]

[0012] [Non-Patent Document 1] Barclay, AN and Brown, MH, Nat Rev Immunol 6, 457-64 (2006) [Non-patent document 2] Shultz, LD et al. (1995) J Immunol 154, 180~91 [Non-patent document 3] Si-Yang Liu et al., J. Hematol. Oncol.10:136(2017) Summary of the Invention [Means for solving the problem]

[0013] The inventors have developed a new approach which involves the assessment of a patient's status for biomarkers that may show predictive value regarding the benefit of cancer treatments involving anti-SIRPα antibodies or antigen-binding fragments thereof, where the assessment is not based on the outcome of blockade of the CD47 / SIRPα system, but is based on the expression levels of specific immune cells, namely CD11b+ / SIRPα+ myeloid cells within the tumor microenvironment, such as tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, in particular MDSCs.

[0014] Higher levels of CD11b expressing SIRPα for stable disease and partial response patients compared with patients with progressive disease at baseline + Myeloid cells are present (baseline = before treatment with anti-SIRPα antibody). High levels of CD11b expressing SIRPα + Myeloid cells drive overall survival better than CD47.

[0015] As shown in the present application, the level of CD11b+ myeloid cells that also express SIRPα in a patient's tumor microenvironment (TME) is associated with better overall survival (OS) and resulting drug efficacy. Thus, the level of CD11b+ / SIRPα+ myeloid cells serves as an important predictive biomarker for patient eligibility for treatment with an anti-SIRPα antibody or antigen-binding fragment thereof. Therefore, the applicant provides a method for detecting CD11b+ myeloid cells that also express SIRPα in the TME. + The level of bone marrow cells has been shown to determine drug efficacy.

[0016] In conclusion, SIRPα from the tumor microenvironment also expresses CD11b + Myeloid cells are more relevant to selecting patients who are more likely to benefit from anti-SIRPα antibodies or their antigen-binding fragments than CD47 expression on tumor cells. Furthermore, the potency of anti-SIRPα antibodies or their antigen-binding fragments is best correlated with SIRPα expression by CD11b+ myeloid cells. At the same time, SIRPα expression on tumor cells was not found to be associated with better overall survival (OS) and resulting drug efficacy.

[0017] Thus, the present invention provides new uses and methods of treating cancer in patients, comprising administering anti-SIRPa compounds, particularly anti-SIRPa antibodies or antigen-binding fragments thereof. In other words, the present invention provides uses of anti-SIRPa compounds, particularly anti-SIRPa antibodies and antigen-binding fragments thereof, and methods in which such compounds are administered to patients with cancer who have been shown to be likely to benefit from or respond positively to such treatment.

[0018] The inventors provide herein uses and methods of administering anti-SIRPα compounds, particularly anti-SIRPα antibodies and antigen-binding fragments thereof, in monotherapy or in combination therapy (concurrently, subsequently, or as primo-therapy) with other therapeutic agents (e.g., but not limited to, immunological agents, such as immune checkpoint inhibitors or activators) and / or treatment methods (e.g., but not limited to, surgery, radiation therapy, chemotherapy, hormone therapy).

[0019] As described in detail in this application, at least two major advances have been made. In accordance with a first aspect, the inventors of the present invention have determined that patients diagnosed with cancer having a tumor whose microenvironment (TME) comprises myeloid cells that express both CD11b and SIRPα are likely to benefit from treatment of their cancer, e.g., exhibit increased overall survival over that expected without treatment, or respond positively to treatment of their cancer, when administered an anti-SIRPα agent, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits the binding between CD47 and SIRPα.

[0020] According to certain embodiments, patients diagnosed with cancer in which at least 55%, particularly at least 60%, particularly at least 65.3% of their bone marrow cells within the tumor microenvironment express the biomarkers CD11b and SIRPα may respond positively to treatment of their cancer by administering an anti-SIRPα agent, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits the binding between CD47 and SIRPα. Because CD47 is normally expressed by tumor cells, it was previously thought that CD47 should be measured to assess whether a therapy based on inhibiting the CD47-SIRPα interaction is likely to be successful; however, in a first aspect of the present invention, the inventors show that overall survival correlates with SIRPα expression in bone marrow cells that express CD11b (p-value <0.05).

[0021] The levels of myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSC, in particular MDSC, that express the biomarkers according to the invention represent measurements performed by immunohistochemistry. Other methods for characterizing markers expressed by cells can be used to measure the levels of myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSC, in particular MDSC, that express the biomarkers according to the invention.

[0022] Typically, determining whether cancer treatment is likely to be successful requires determining or measuring the expression of biomarkers by tumor cells, rather than by the patient's bone marrow cells. The inventors have discovered that positive clinical outcomes or responses are observed in patients with at least 55%, particularly at least 60%, particularly at least 65.3% CD11b-positive and SIRPα-positive bone marrow cells, compared with patients with less than 60%, particularly less than 65.3% CD11b-positive and SIRPα-positive bone marrow cells. The percentage of bone marrow cells expressing CD11b and SIRPα is associated with better overall survival (OS) and better efficacy of treatment in patients treated with anti-SIRPα antagonist antibodies (either monotherapy or combination therapy). Therefore, CD11b-positive and SIRPα-positive bone marrow cells (also referred to as CD11+ / SIRPα+ bone marrow cells) are important predictive biomarkers for selecting or targeting patients who may benefit from treatment involving the administration of anti-SIRPα antagonist antibodies or their antigen-binding fragments.

[0023] In certain embodiments, CD11b- and SIRPa-expressing myeloid cells in the TME are measured prior to administering treatment to the patient, particularly prior to administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof that inhibits binding between SIRPa and CD47. Measurement of CD11b- and SIRPa-expressing myeloid cells in the tumor microenvironment (TME) prior to treatment is therefore considered a measurement of baseline levels of CD11b+ and SIRPα+ myeloid cells.

[0024] In certain embodiments, myeloid cells expressing CD11b and SIRPa in the TME are measured during administration of treatment to the patient, particularly during administration of an anti-SIRPa antibody or antigen-binding fragment thereof that inhibits the binding between SIRPa and CD47 to the patient. Measurement of myeloid cells expressing CD11b and SIRPa in the tumor microenvironment (TME) during treatment is therefore considered a measurement of baseline levels of CD11b+ and SIRPa+ myeloid cells. By during treatment, it is meant that several administrations are planned (at least two), and measurements are taken with or after the first administration and before the last planned administration.

[0025] Provided is a composition comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating cancer in a patient, wherein the cancer is characterized by a tumor whose microenvironment (TME) comprises myeloid cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, particularly MDSCs, that express both CD11b and SIRPα.

[0026] In certain embodiments, compositions are provided comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating cancer in a patient, wherein the cancer is characterized by a tumor whose microenvironment (TME) comprises tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs that express both CD11b and SIRPα. Each of the tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs may be considered a subpopulation of myeloid cells.

[0027] In a particular embodiment, the composition is for use in treating cancer in a patient, wherein the cancer is characterized by a tumor having a tumor microenvironment (TME) in which at least 55%, particularly at least 60%, preferably at least 65.3% of myeloid cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs present within the tumor microenvironment, particularly MDSCs, express the biomarkers CD11b and SIRPα when tested by immunohistochemistry (IHC).

[0028] In a further embodiment of the described uses, the patient's tumor microenvironment comprises tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs expressing the biomarkers CD11b and SIRPα.

[0029] In a further embodiment of the described uses, the patient's tumor microenvironment comprises tumor-associated macrophages expressing the biomarkers CD11b and SIRPα.

[0030] In a further embodiment of the described uses, the patient's tumor microenvironment comprises monocytes expressing the biomarkers CD11b and SIRPα.

[0031] In a further embodiment of the described uses, the patient's tumor microenvironment comprises myeloid dendritic cells expressing the biomarkers CD11b and SIRPα.

[0032] In a further embodiment of the described uses, the patient's tumor microenvironment comprises tumor-associated neutrophils expressing the biomarkers CD11b and SIRPα.

[0033] In a further embodiment of the described uses, the patient's tumor microenvironment comprises tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and MDSCs that express the biomarkers CD11b and SIRPα.

[0034] In certain embodiments, the patient has bone marrow cells within the tumor microenvironment, said bone marrow cells comprising tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, in particular MDSCs.

[0035] In certain embodiments, there is provided a composition comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating a patient with cancer, wherein the patient: - myeloid cells, in which at least 55%, in particular at least 60%, in particular at least 65.3% of the myeloid cells present in the tumor microenvironment, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, express the biomarkers CD11b and SIRPα. Accordingly, the present invention also provides a composition comprising an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in a method of treating cancer in a patient having cancer, wherein the method comprises: - determining the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, expressing CD11b and SIRPα in a biological sample obtained from the patient, wherein the myeloid cells are myeloid cells from the tumor microenvironment, - if at least 55%, in particular at least 60%, in particular at least 65.3% of the myeloid cells present in the tumor microenvironment, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, express the biomarkers CD11b and SIRPα, - administering a treatment comprising an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The present invention relates to a composition comprising:

[0036] In a particular embodiment, the composition for use according to the invention as disclosed in the various embodiments is a composition for the treatment of liquid or solid cancer, in particular cancer with advanced solid tumors, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, in particular ovarian cancer, colorectal cancer or non-small cell lung cancer (NSCLC).

[0037] In a third aspect of the present invention, the inventors have discovered that the presence or absence, respectively, of specific immune cells having the determined predictive biomarkers disclosed herein within a patient's tumor microenvironment is associated with clinical benefit, particularly a positive or negative response of the patient to treatment for cancer with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, particularly in combination with a second therapeutic agent.

[0038] Thus, there is provided a composition comprising an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for simultaneous or subsequent administration with a therapeutic agent selected from immune checkpoint inhibitors of the interaction between tumor cells and myeloid cells, in particular a compound that inhibits the interaction between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, such as an anti-PD1 or anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody, or with a compound that targets lymphocyte activation gene-3 (LAG-3), in particular an antibody against lymphocyte activation gene-3, for use in the treatment of patients with cancer who are likely to respond positively to treatment according to the test provided by the present invention.

[0039] In certain embodiments, the patient has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs within the tumor microenvironment.

[0040] In certain embodiments, the patient has tumor-associated macrophages within the tumor microenvironment.

[0041] In certain embodiments, the patient has monocytes within the tumor microenvironment.

[0042] In certain embodiments, the patient has myeloid dendritic cells within the tumor microenvironment.

[0043] In certain embodiments, the patient has tumor-associated neutrophils within the tumor microenvironment.

[0044] In certain embodiments, the patient has MDSCs within the tumor microenvironment.

[0045] In certain embodiments, the patient has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and MDSCs within the tumor microenvironment.

[0046] Administration of an anti-SIRPα antibody may result in increased expression of PD-1 and / or PD-L1 within tumors. Thus, the combined use of an anti-SIRPα antibody with an anti-PD-L1 antibody or an anti-PD-1 antibody may be useful in treating certain types of cancer, particularly cancers that have been shown to be resistant to monotherapy treatment. Anti-SIRPα antibodies have been shown to be positive for the CD11b and SIRPα biomarkers according to the present invention, and optionally result in an enhanced anti-tumor effect of anti-PD-L1 antibodies or anti-PD-1 antibodies in patients who have tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly MDSCs, within the tumor microenvironment.

[0047] The use of the anti-SIRPα antibodies or antigen-binding fragments thereof disclosed herein enhances the presence of immune cells within the tumor microenvironment. Administration of the anti-SIRPα antibodies or antigen-binding fragments increases the expression of certain markers, such as PD-L1, which may enhance the use of other therapies in combination with the administration of the anti-SIRPα agent. The inventors have shown that such combinations of therapeutic agents are particularly effective in patients who have tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly MDSCs, within the tumor microenvironment.

[0048] According to one aspect of the invention, a method is provided for assessing a patient's status for a biomarker of response to treatment with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for cancer involving a solid tumor, and the method comprises: - providing a biological sample previously obtained from the patient, the sample being a sample from the patient's tumor microenvironment (TME) and comprising bone marrow cells, in particular the sample being a biopsy specimen of the patient's tumor microenvironment; - determining the presence in the biological sample of myeloid cells expressing the CD11b and SIRPα biomarkers, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and MDSCs, in particular MDSCs, that express the CD11b and SIRPα biomarkers; Includes.

[0049] According to certain embodiments, there is also provided a method for determining whether a patient having cancer is likely to benefit from a therapy to treat the cancer, comprising: - providing a biological sample previously obtained from the patient, the sample being a sample from the patient's tumor microenvironment (TME) and comprising bone marrow cells, in particular the sample being a biopsy specimen of the patient's tumor microenvironment; - determining or measuring the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, that express CD11b and SIRPα in a biological sample; Including, - the patient is likely to benefit from the treatment if myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, that express the CD11b and SIRPα biomarkers are present in the biological sample; A method is provided.

[0050] In certain embodiments, if the percentage of bone marrow cells expressing CD11b and SIRPα is at least 55%, particularly at least 60%, particularly at least 65.3% in the biological sample, the patient is classified as likely to respond positively to treatment of their cancer by administration of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0051] According to certain embodiments, there is also provided a method for distinguishing between patients with cancer who are likely to respond positively to treatment of their cancer by administration of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and those who are not, comprising: - providing a biological sample previously obtained from the patient, the sample being a sample from the patient's tumor microenvironment (TME) and comprising bone marrow cells, in particular the sample being a biopsy specimen of the patient's tumor microenvironment; - determining or measuring the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, tumor-associated neutrophils, that express CD11b and SIRPα in a biological sample; Including, - if myeloid cells expressing the CD11b and SIRPα biomarkers are present in the biological sample, the patient is likely to benefit from the treatment and / or the patient is likely to respond positively to the treatment; A method is provided.

[0052] In certain embodiments, patients who are likely to respond positively to treatment are those who have at least 55%, particularly at least 60%, particularly 65.3% of bone marrow cells in their biological sample that express CD11b and SIRPα.

[0053] According to certain embodiments, there is also provided a method of treating cancer in a patient having cancer, comprising: - providing a biological sample previously obtained from the patient, the sample being a sample from the patient's tumor microenvironment (TME) and comprising bone marrow cells, in particular the sample being a biopsy specimen of the patient's tumor microenvironment; - determining the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, that express CD11b and SIRPα in the biological sample, - if myeloid cells expressing CD11b and SIRPα biomarkers are present in the biological sample, administering to the patient an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, alone or in combination with a therapeutic agent selected from immune checkpoint inhibitors of the interaction between tumor cells and myeloid cells, in particular a compound that inhibits the interaction between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, such as an anti-PD1 or anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody, or in combination treatment with a compound that targets lymphocyte activation gene-3 (LAG-3), in particular an antibody against lymphocyte activation gene-3. A method is provided that includes:

[0054] In a particular embodiment of this method, the percentage of bone marrow cells expressing CD11b and SIRPα is at least 55%, particularly at least 60%, in particular at least 65.3% in the biological sample.

[0055] In certain embodiments of the methods of treating cancer, the patient is administered an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, in combination treatment with a second therapeutic agent, particularly an anti-PD1 or anti-PD-L1 antibody.

[0056] In a particular embodiment of this method of treatment, the patient has liquid or solid cancer, in particular cancer with advanced solid tumors, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, in particular ovarian cancer, colorectal cancer or non-small cell lung cancer (NSCLC).

[0057] According to certain embodiments, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in the treatment of cancer associated with solid tumors, particularly cancer associated with advanced solid tumors, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, wherein the patient is identified for exhibiting a biomarker disclosed by the present invention.

[0058] According to certain embodiments, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in combination with an immune checkpoint inhibitor or activator in the treatment of cancer, wherein the patient is identified for displaying the predictive biomarkers disclosed by the present invention.

[0059] According to a particular embodiment, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in treating patients who are known or shown prior to use to be non-responsive to cancer treatment or therapy and / or who have shown cancer disease progression despite being on treatment. According to this embodiment, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in treating cancer in patients who have failed treatment with at least one alternative cancer therapeutic agent or method of treatment, wherein the patient is identified for displaying the predictive biomarkers disclosed by the present invention.

[0060] According to a specific embodiment, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in treating a patient who has not previously been treated. According to this embodiment, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in treating cancer in a patient as a first line of therapy.

[0061] According to certain embodiments, the present invention provides an anti-SIRPα antibody or antigen-binding fragment thereof for use in treating patients who have been treated with an immune checkpoint inhibitor or activator, particularly an anti-PD-1 or anti-PD-L1 agent, and who have failed to respond positively or maintain a response to administration of the immune checkpoint inhibitor or activator (i.e., the patient shows disease progression and / or does not show disease regression), wherein the patient is identified for displaying a biomarker disclosed by the present invention. [Brief explanation of the drawings]

[0062] [Figure 1]1 shows the absence of a correlation between overall patient survival and CD47 expression on tumor cells. Patients with low CD47 expression (compared to the median CD47 expression in the patient pool) are indicated by a black dotted line. Patients with high CD47 expression (compared to the median CD47 expression in the patient pool) are indicated by a light gray line. The solid line corresponds to the mean value of either all high CD47 expressing patients or all low CD47 expressing patients. Time is in months. Survival probability is assessed over time by comparing the number of surviving patients to the total number of patients at the start of the study. A) Mean values ​​for all treated patients (by anti-SIRPα antibody monotherapy or by combination therapy with an anti-SIRPα antibody (comprising the heavy chain variable domain of SEQ ID NO: 8 and the light chain variable domain of SEQ ID NO: 10; this anti-SIRPα antibody was used in all experiments disclosed herein) and a PD1 inhibitor (the anti-PD1 antagonist antibody ezabenlimab) are shown. B) Mean values ​​for patients treated with anti-SIRPα antibody monotherapy are shown. [Figure 2] Figure 1 shows the absence of a correlation between overall patient survival and SIRPα expression in tumor cells. Patients with low expression of SIRPα (compared to the median expression of SIRPα in the pool of patients) are indicated by a black dotted line. Patients with high expression of SIRPα (compared to the median expression of SIRPα in the pool of patients) are indicated by a light gray line. The solid line corresponds to the mean value of either all patients with high SIRPα expression or all patients with low SIRPα expression. Time is in months. Survival probability is assessed by comparing the number of surviving patients over time with the total number of patients at the start of the study. A) Shows the mean value of all treated patients (by monotherapy with an anti-SIRPα antibody or by combination therapy with an anti-SIRPα antibody and a PD1 inhibitor), as defined in the legend to Figure 1. B) Shows the mean value of patients treated by monotherapy with an anti-SIRPα antibody, as defined in the legend to Figure 1. [Figure 3-1]A) Correlation between overall patient survival and SIRPα expression in CD11b-positive bone marrow cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 65.3% of CD11b+SIRPa+ bone marrow cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 65.3% of CD11b+SIRPa+ bone marrow cells) are represented by a light gray line. Mean values ​​are shown for all treated patients (by monotherapy with anti-SIRPα antibody or by combination therapy with anti-SIRPα antibody and PD1 inhibitor), as defined in the legend to Figure 1. B) Correlation between overall patient survival and SIRPα expression in CD11b-positive bone marrow cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 65.3% of CD11b+SIRPa+ bone marrow cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 65.3% of CD11b+SIRPa+ bone marrow cells) are represented by a light gray line. The mean values ​​for patients treated with anti-SIRPα antibody monotherapy, as defined in the legend to FIG. 1, are shown. [Figure 3-2] C) Correlation between overall patient survival and SIRPα expression in CD11b-positive bone marrow cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 60% of CD11b+SIRPa+ bone marrow cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 60% of CD11b+SIRPa+ bone marrow cells) are represented by a light gray line. Mean values ​​are shown for all treated patients (by monotherapy with anti-SIRPα antibody or by combination therapy with anti-SIRPα antibody and PD1 inhibitor), as defined in the legend to Figure 1. D) Correlation between overall patient survival and SIRPα expression in CD11b-positive bone marrow cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 60% of CD11b+SIRPa+ bone marrow cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 60% of CD11b+SIRPa+ bone marrow cells) are represented by a light gray line. The mean values ​​for patients treated with anti-SIRPα antibody monotherapy, as defined in the legend to FIG. 1, are shown. [Figure 3-3]E) Correlation between overall patient survival and SIRPα expression in CD11b-positive myeloid cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 55% of CD11b+SIRPα+ myeloid cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 55% of CD11b+SIRPα+ myeloid cells) are represented by a light gray line. The solid line corresponds to the mean value of either all high-SIRPα expressing patients or all low-SIRPα expressing patients. The dotted line corresponds to the standard deviation for each group of patients. Survival probability is assessed over time by comparing the number of surviving patients with the total number of patients at the start of the study. The mean values ​​for all treated patients (by monotherapy with anti-SIRPα antibody or by combination therapy with anti-SIRPα antibody and PD1 inhibitor) are shown, as defined in the legend to Figure 1. F) Correlation between overall patient survival and SIRPα expression in CD11b-positive myeloid cells derived from the tumor microenvironment. Patients with low SIRPα expression (less than 55% of CD11b+SIRPa+ bone marrow cells) are represented by a black dotted line. Patients with high SIRPα expression (at least 55% of CD11b+SIRPa+ bone marrow cells) are represented by a light gray line. The solid line corresponds to the mean value of either all high-SIRPα expressing patients or all low-SIRPα expressing patients. The dotted line corresponds to the standard deviation of each group of patients. Survival probability is assessed over time by comparing the number of surviving patients with the total number of patients at the start of the study. The mean value of patients treated with anti-SIRPα antibody monotherapy, as defined in the legend to Figure 1, is shown. [Figure 4] FIG. 1 shows the correlation of gene expression profiles in patients who respond positively to combination therapy of anti-SIRPα antibody and PD1 inhibitor (abscissa and left part) with known gene expression profiles in MDSCs (ordinate and right part). DETAILED DESCRIPTION OF THE INVENTION

[0063] ·Definition As used herein, the term "antibody" refers to any type of antibody, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a chimeric antibody, or a humanized antibody. The term "antibody" can also refer to a deimmunized antibody, i.e., an antibody in which T cell epitopes have been removed from the antibody's structure without significantly reducing the antibody's binding affinity to its target SIRPα. Typically, a "deimmunized" antibody is generated with a human constant region. The antibodies of the present invention include monoclonal and polyclonal antibodies. As used herein, "monoclonal antibody" is intended to refer to a preparation of antibody molecules that share a common heavy chain and a common light chain amino acid sequence, in contrast to a "polyclonal" antibody preparation, which contains a mixture of antibodies with different amino acid sequences. Monoclonal antibodies can be generated by several known techniques, such as phage, bacterial, yeast, or ribosome display, as well as classical methods exemplified by hybridoma-derived antibodies. Thus, the term "monoclonal" is used to refer to all antibodies derived from a single nucleic acid clone. The antibodies of the present invention include recombinant antibodies. As used herein, the term "recombinant antibody" refers to an antibody that is produced, expressed, generated, or isolated by recombinant means, e.g., an antibody expressed using a recombinant expression vector transfected into a host cell; an antibody isolated from a recombinant combinatorial antibody library; an antibody isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes; or an antibody produced, expressed, generated, or isolated in any other way in which particular immunoglobulin gene sequences (e.g., human immunoglobulin gene sequences) are assembled with other DNA sequences. Recombinant antibodies include, for example, chimeric and humanized antibodies. Antibodies of the present invention include chimeric antibodies. As used herein, "chimeric antibody" refers to an antibody in which variable domain sequences derived from the germline of a mammalian species, e.g., a mouse, have been grafted onto constant domain sequences derived from the germline of another mammalian species, e.g., a human. Antibodies of the present invention include humanized antibodies.As used herein, "humanized antibody" refers to an antibody in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0064] As used herein, "antigen-binding fragment of an antibody" refers to a molecule corresponding to a portion of the antibody's structure, i.e., a molecule that likely exhibits antigen-binding ability for SIRPα in its native form; such a fragment particularly exhibits the same or substantially the same antigen-binding specificity for the antigen as that of the corresponding four-chain antibody. Advantageously, the antigen-binding fragment has a binding affinity similar to that of the corresponding four-chain antibody. However, antigen-binding fragments with reduced antigen-binding affinity for the corresponding four-chain antibody are also encompassed by the present invention. The antigen-binding ability can be determined by measuring the affinity between the antibody and the target fragment. These antigen-binding fragments may also be referred to as "functional fragments" of antibodies. Antigen-binding fragments of antibodies include their hypervariable domains or parts thereof, called CDRs (complementarity-determining regions), which encompass the recognition site for the antigen, i.e., the extracellular domain of SIRPα, thereby defining the antigen recognition specificity. Antigen-binding fragments of antibodies containing variable domains including the antibody CDRs include Fv, dsFv, scFv, Fab, Fab', and F(ab')2. Fv fragments consist of the VL and VH domains of an antibody that are associated together by hydrophobic interactions; in dsFv fragments, the VH:VL heterodimer is stabilized by a disulfide bond; in scFv fragments, the VL and VH domains are connected to each other by a flexible peptide linker, thus forming a single-chain protein. Fab fragments are monomeric fragments obtainable by papain digestion of antibodies; they contain the entire L chain and the VH-CH1 fragment of the H chain, linked together by a disulfide bond. F(ab')2 fragments can be produced by pepsin digestion of antibodies below the hinge disulfide; they contain two Fab' fragments and, in addition, a portion of the hinge region of an immunoglobulin molecule. Fab' fragments can be obtained from F(ab')2 fragments by cleaving the disulfide bond in the hinge region.F(ab')2 fragments are bivalent, i.e., they contain two antigen-binding sites like native immunoglobulin molecules; on the other hand, Fv (VHVL dimers consisting of the variable portions of Fab), dsFv, scFv, Fab, and Fab' fragments are monovalent, i.e., they contain a single antigen-binding site. These basic antigen-binding fragments of the invention can be combined together to obtain multivalent antigen-binding fragments such as diabodies, tribodies, or tetrabodies. These multivalent antigen-binding fragments are also part of the present invention.

[0065] The composition may particularly refer to a pharmaceutical composition. When used for systemic or local administration, such a composition may contain pharmaceutically acceptable ingredients, such as, but not limited to, a pharmaceutically suitable excipient, carrier, or vehicle. A pharmaceutically suitable carrier or vehicle refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, and formulation, such as phosphate buffered saline solution, distilled water, emulsions such as oil / water emulsions, wetting agents, dextrose, saline, ethanol, and combinations thereof.

[0066] As used herein, the term "SIRPα" refers to signal-regulatory peptide alpha from mammalian species, preferably human SIRPα. SIRPα is also referred to as CD172a, tyrosine-protein phosphatase non-receptor substrate 1, or SHPS-1. SIRPα is an immunoglobulin-like cell surface receptor for CD47. SIRPα acts as a docking protein, inducing the translocation of PTPN6, PTPN11, and other binding partners from the cytosol to the plasma membrane. SIRPα mediates negative regulation of phagocytosis, mast cell activation, and dendritic cell activation. Binding of CD47 to SIRPα prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. SIRPα may correspond to the protein referenced by Uniprot number P78324. Alternatively, SIRPα may correspond to a protein having the amino acid sequence of SEQ ID NO: 1. The extracellular domain of SIRPα that is likely to be recognized and bound by the anti-SIRPα antibodies or antigen-binding fragments thereof that are agents used in the present invention may correspond to the amino acid sequence of SEQ ID NO:2.

[0067] As used herein, the term "CD11b" refers to cluster of differentiation molecule 11B. It is also known as integrin alpha M (ITGAM), macrophage-1 antigen (Mac-1), or complement receptor 3 (CR3). ITGAM is also known as CR3A. CD11b is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 (αMβ2) molecule. CD11b is used to identify myeloid cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly MDSCs. Human CD11b may have the amino acid sequence associated with Uniprot reference number P11215 or may correspond to the amino acid sequence of SEQ ID NO: 14.

[0068] The terms "cancer" and "tumor" have their common meaning in the art and refer to a group of diseases involving abnormal cell growth and having the potential to invade or spread to other parts of the body. The term "cancer" further encompasses both primary and metastatic cancers. Cancer is a disease involving abnormal cell growth that has the potential to invade or spread to other parts of the body. In accordance with the present invention, the cancer that the patient is suffering from or has suffered from may be selected from the list consisting of bladder cancer, bone cancer, brain cancer, breast cancer including triple-negative breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin's lymphoma, leukemia, liver cancer, lung cancer including non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, myelodysplastic syndrome, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, adrenal cancer, biliary tract cancer, colorectal cancer, gastrointestinal cancer, renal cancer, parotid gland cancer or uterine cancer, especially ovarian cancer, breast cancer, especially triple-negative breast cancer, liver cancer, hepatocellular carcinoma, endometrial cancer or uterine cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer. In certain embodiments, the cancer the patient is suffering from is breast cancer, ovarian cancer, liver cancer, endometrial cancer, or hepatocellular carcinoma. The tumor microenvironment is the ecosystem surrounding a tumor in the body. It includes immune cells, extracellular matrix, blood vessels, and other cells such as fibroblasts. The tumor microenvironment includes the space surrounding the tumor and includes surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix. The tumor and the surrounding microenvironment are closely related and constantly interact. Immune cells in the microenvironment can influence the growth and evolution of cancerous cells.

[0069] As used herein, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease, preventing or slowing the recurrence or relapse of the disease, slowing or slowing the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, allowing for a reduction in the administered dose of one or more other medications needed or used to treat the disease, increasing quality of life, allowing for progression-free survival (PFS), increasing the time to disease progression, and / or prolonging survival, particularly overall survival (OS), and preventing or mitigating side effects of current or to-be-developed treatments.

[0070] The term "effective dose" or "effective administration amount" or "effective amount" or "therapeutically effective dose" is defined as an amount sufficient to achieve or at least partially achieve the desired effect. The term "effective dose" is meant to encompass an amount sufficient to cure or at least partially prevent the disease and its complications, or to alleviate the symptoms of the disease in a patient already suffering from the disease. The amount or dose effective for this use will depend on the condition to be treated, the antibody construct being delivered, the therapeutic situation and therapeutic objectives, the severity of the disease, previous treatments, the patient's clinical history and response to the therapeutic agent, the route of administration, the patient's size (weight, body surface, or organ size) and / or condition (age and health), and the overall state of the patient's own immune system. The appropriate dose can be adjusted to obtain the optimal therapeutic effect, such that it can be administered to the patient at one time or over a series of administrations. In certain embodiments, an effective dose is one that allows a reduction in tumor volume (or tumor shrinkage) or the absence of tumor volume progression in the treated patient. As an example, a "therapeutically acceptable amount" of a therapeutic agent such as an antibody or antigen-binding fragment thereof may comprise from about 0.1 mg to about 50 mg of agent per kg of patient body weight (agent / patient body weight).

[0071] A "marker" (or biomarker) is defined as a biochemical molecule or cellular alteration that can be measured in a biological tissue, such as a tissue, cell, or fluid, and that is indicative of, e.g., functionally related to, the normal or abnormal process of a condition or disease. The term "biomarker" refers to a molecule that can be accurately and reproducibly measured, thereby providing a "signature" that can be objectively measured and evaluated as an indicator of a normal biological process or a pathogenic process or a pharmacological response. In the context of the present invention, a biomarker corresponds to a biomolecule expressed by and / or present in a human cell. Thus, in the context of the present invention, biomarkers include protein biomarkers, genetic biomarkers (corresponding to the transcription products of genes), and epigenetic biomarkers (e.g., corresponding to DNA methylation). In the context of the present invention, biomarkers include DNA, RNA, and protein. CD11b and SIRPα are considered markers in the context of the present invention.

[0072] The patient may be any human who has had, is suspected of having, or will develop cancer. In particular, the subject may be any human who has cancer and has been diagnosed as such. The patient may be a child, adolescent, or adult. The subject may or may not be being treated for symptoms associated with cancer. In one embodiment of the present invention, the subject is or has been treated for cancer, for example, by chemotherapy, radiation therapy, immunotherapy, hormonal therapy, or any suitable method. In another embodiment of the present invention, the subject is not or has not yet been treated for cancer. The present invention may optionally include determining one or more clinical factors of the subject, such as factors selected from gender, age, body mass index, and medical history.

[0073] The biological sample obtained from a patient can be any biological sample, such as tissue, blood, urine, whole cell lysate, biopsy specimen, tumor, or tumor cells. Methods for obtaining biological samples from patients are well known in the art and include obtaining samples from surgically removed tissue. Tissue, blood, urine, biopsy specimen, tumor, and cell samples can also be obtained without the need for invasive surgery, for example, by puncturing a subject with a fine needle and withdrawing cellular material, or by biopsy. In certain embodiments, the sample taken from a patient can be processed or treated to obtain a processed biological sample, such as a supernatant, whole cell lysate, or fraction or extract of cells obtained directly from the patient. In other embodiments, the biological sample from the patient can also be used without further treatment or processing. In a preferred embodiment, the biological sample obtained from a patient is tissue, particularly tissue from a tumor or tumor extract, preferably tissue obtained by biopsy. A biological sample derived from a subject may be, for example, a sample removed or collected or ready to be removed or collected from an organ or tissue or tumor of said subject, in particular a tumor, or a biological fluid from said subject, such as blood, serum, plasma, tumor microenvironment or urine. A biological sample collected or removed from a subject may be, for example, a sample containing cancer cells removed or collected or ready to be removed or collected from a tissue, in particular a tumor, of said subject. A step for lysis of cells contained in said biological sample, in particular lysis of cancer cells, may be carried out beforehand so that nucleic acids, or, where appropriate, proteins and / or polypeptides and / or peptides, are directly available for analysis.

[0074] As used herein, "myeloid cells" refer to blood cells or tumor microenvironment cells that arise from precursor cells of granulocytes, monocytes, dendritic cells, erythrocytes, or platelets. Myeloid cells include macrophage cells, MDSCs and myeloid dendritic cells, eosinophilic cells, neutrophilic cells, basophilic cells, erythroid cells, and platelet cells. In certain embodiments, myeloid cells refer to tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils.

[0075] ·Anti-SIRPα compounds Compositions to be used according to the invention or in methods according to the invention comprise anti-SIRPα compounds, in particular anti-SIRPα antibodies or antigen-binding fragments thereof, that inhibit the binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The term "anti-SIRPα compound" encompasses both anti-SIRPα antibodies and antigen-binding fragments thereof that inhibit the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0076] In certain embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof is an antagonist of the binding between SIRPα and CD47; i.e., it reduces the interaction between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0077] In certain embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof is an antagonist of the signal transduction pathway induced by the interaction between SIRPα and CD47; i.e., it reduces or inhibits an intracellular molecular pathway that is normally activated in the absence of the anti-SIRPα antibody or antigen-binding fragment thereof when SIRPα and CD47 interact.

[0078] In a preferred embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof does not inhibit the interaction between human SIRPα and human CD47.

[0079] In certain embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof specifically binds to human SIRPα v1 and human SIRPα v2, allowing treatment of patients expressing any combination of SIRPa alleles selected from SIRPα v1 and SIRPα v2.

[0080] In certain embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof does not specifically bind to human SIRPγ, and in particular does not reduce or inhibit the interaction between human CD47 and human SIRPγ. In particular, the anti-SIRPα antibody or antigen-binding fragment thereof is not an antagonist of the human CD47 / human SIRPγ interaction.

[0081] An antibody or antigen-binding fragment thereof can be considered to inhibit the interaction between SIRPα and CD47 if the antibody or antigen-binding fragment thereof has an antagonistic effect on the CD47 / SIRPα interaction. When used in the negative form, for example, when an antibody, respectively, an antigen-binding fragment thereof does not inhibit the interaction between human SIRPα and human CD47, it means that the antibody, respectively, an antigen-binding fragment thereof does not have an antagonistic effect on the CD47 / SIRPα interaction. Reducing or inhibiting the binding of CD47 (human CD47) to SIRPα (human SIRPα) means that the antibody or antigen-binding fragment thereof, or antigen-binding antibody mimetic, or modified antibody reduces the interaction between SIRPα and CD47, i.e., the antibody or antigen-binding fragment thereof partially or completely inhibits the binding of human CD47 to human SIRPα, or in other words, specifically binds to human SIRPα and antagonizes the interaction between human SIRPα and human CD47. In particular, the anti-human SIRPα antibody or antigen-binding fragment thereof has the ability to reduce or inhibit the binding of CD47 (human CD47) to SIRPα (human SIRPα) in a binding assay by at least 50%, preferably 60%, more preferably 70%, more preferably 80%, and most preferably 90%, and in certain embodiments, 100%, compared to a negative control molecule. In particular, the anti-SIRPα antibody or antigen-binding fragment thereof has the ability to reduce or inhibit the binding of human CD47 to human SIRPα in a binding assay by 50% to 100%, more preferably 50% to 90%, compared to a negative control molecule.

[0082] In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof is an anti-SIRPα antagonist antibody or antigen-binding fragment thereof that antagonizes (i.e., reduces or inhibits) the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0083] In certain embodiments of the invention, the anti-SIRPα antibody or antigen-binding fragment thereof i) a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5; or SEQ ID NO:6; or SEQ ID NO:7; or SEQ ID NO:8; ii) a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10 Includes.

[0084] In certain embodiments of the invention, the anti-SIRPα antibody or antigen-binding fragment thereof i) - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 18 or SEQ ID NO: 19 or SEQ ID NO: 20 or SEQ ID NO: 21 a heavy chain variable domain comprising: ii) - a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 a light chain variable domain comprising Includes.

[0085] In certain embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof is - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 17; and - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 21 a heavy chain variable domain comprising: a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 a light chain variable domain comprising Includes.

[0086] In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof is a monoclonal antibody. In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof is a humanized antibody. In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof is a humanized monoclonal antibody. In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof is selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), double-chain variable fragment (dsFv), and (Fab')2 fragment. In particular, the antibody or antigen-binding fragment thereof comprises a constant chain belonging to the IgG1, IgG2, IgG3, or IgG4 subclass, particularly the IgG1 or IgG4 subclass, and especially the IgG4 subclass.

[0087] In certain embodiments of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:10.

[0088] In certain embodiments of the invention, the anti-SIRPα antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:10.

[0089] In certain embodiments of the invention, the anti-SIRPα antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:11 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12.

[0090] In certain embodiments of the invention, the anti-SIRPα antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:11 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12.

[0091] In certain embodiments of the invention, the anti-SIRPα antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:13 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12.

[0092] In certain embodiments of the invention, the anti-SIRPα antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:13 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12.

[0093] In certain embodiments of the present invention, anti-SIRPα antibodies or antigen-binding fragments thereof that can be used in the disclosed invention include SEQ ID NO: 8 and SEQ ID NO: 9 of WO2020 / 099653, or SIRPa-binding portions thereof, such as antigen-binding fragments of anti-SIRPa antibodies, anti-SIRPa antibodies or antigen fragments containing the above-mentioned CDRs, which may optionally be linked to a pharmacokinetic enhancer.

[0094] Additional exemplary anti-SIRPa antibodies that can be used in the disclosed invention include SEQ ID NO: 7 and SEQ ID NO: 8 of WO2019 / 023347, or SEQ ID NO: 15 and SEQ ID NO: 16 of WO2019 / 023347, or a SIRPa-binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen-binding fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0095] In a specific embodiment of the present invention, the disclosed anti-SIRPα antibody or antigen-binding fragment thereof that can be used in the present invention may be an antibody disclosed in the PCT publication published under reference WO2022 / 254379, particularly any one of the antibodies designated A, A4, A10, A11, E, and E22, particularly an anti-SIRPα antibody or antigen-binding fragment thereof comprising CDRs disclosed in any one of Tables 1 to 10 of WO2022 / 254379, and in particular, the anti-SIRPα antibody or antigen-binding fragment thereof may be an anti-SIRPα antibody or antigen-binding fragment thereof comprising CDRs set forth in SEQ ID NO: 100 or SEQ ID NO: 100 of WO2022 / 254379. 11 or SEQ ID NO: 113 or SEQ ID NO: 104 or SEQ ID NO: 221 and a light chain variable region of SEQ ID NO: 105 or SEQ ID NO: 125 or SEQ ID NO: 126 or SEQ ID NO: 109 or SEQ ID NO: 222 of WO2022 / 254379, or has a heavy chain of SEQ ID NO: 131 or SEQ ID NO: 135 or SEQ ID NO: 141 or SEQ ID NO: 147 or SEQ ID NO: 217 or SEQ ID NO: 219 and a light chain of SEQ ID NO: 174 or SEQ ID NO: 178 or SEQ ID NO: 184 or SEQ ID NO: 190 or SEQ ID NO: 218 or SEQ ID NO: 220. In particular, an anti-SIRPα antibody or antigen-binding fragment thereof that can be used in the disclosed invention may have any one of the following combinations of heavy chain variable regions and light chain variable regions: SEQ ID NO: 100 and SEQ ID NO: 105, or SEQ ID NO: 104 and SEQ ID NO: 109, or SEQ ID NO: 113 and SEQ ID NO: 125, or SEQ ID NO: 111 and SEQ ID NO: 126, or SEQ ID NO: 221 and SEQ ID NO: 222. In particular, an anti-SIRPα antibody or antigen-binding fragment thereof that may be used in the disclosed invention may have any one of the following combinations of heavy and light chains: SEQ ID NO: 131 and SEQ ID NO: 174, or SEQ ID NO: 135 and SEQ ID NO: 178, or SEQ ID NO: 141 and SEQ ID NO: 184, or SEQ ID NO: 147 and SEQ ID NO: 190, or SEQ ID NO: 217 and SEQ ID NO: 218, or SEQ ID NO: 219 and SEQ ID NO: 220.

[0096] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention include SEQ ID NO: 80 and SEQ ID NO: 67 of WO2020 / 068752, SEQ ID NO: 85 and SEQ ID NO: 67 of WO2020 / 068752, or SEQ ID NO: 138 and SEQ ID NO: 127 of WO2020 / 068752, or a SIRPa-binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen-binding fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0097] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention are SEQ ID NO: 105 and SEQ ID NO: 124 of WO2021 / 226576; SEQ ID NO: 108 and SEQ ID NO: 127 of WO2021 / 226576; SEQ ID NO: 109 and SEQ ID NO: 128 of WO2021 / 226576; SEQ ID NO: 119 and SEQ ID NO: 138 of WO2021 / 226576; SEQ ID NO: 120 and SEQ ID NO: 139 of WO2021 / 226576; SEQ ID NO: 140 and SEQ ID NO: 141 of WO2021 / 226576; 121 and SEQ ID NO: 140; SEQ ID NO: 122 and SEQ ID NO: 141 of WO2021 / 226576; optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3 or IgG4 constant region or a variant thereof), a SIRPa binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0098] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention are SEQ ID NO: 104 and SEQ ID NO: 123 of WO2021 / 226591; SEQ ID NO: 106 and SEQ ID NO: 125 of WO2021 / 226591; SEQ ID NO: 107 and SEQ ID NO: 126 of WO2021 / 226591; SEQ ID NO: 110 and SEQ ID NO: 129 of WO2021 / 226591; SEQ ID NO: 111 and SEQ ID NO: 130 of WO2021 / 226591; SEQ ID NO: 112 and SEQ ID NO: 131 of WO2021 / 226591; SEQ ID NO: 113 and SEQ ID NO: 132 of WO2021 / 226591; SEQ ID NO: 114 and SEQ ID NO: 133 of WO2021 / 226591 No. 133; SEQ ID NO: 115 and SEQ ID NO: 134 of WO2021 / 226591; SEQ ID NO: 116 and SEQ ID NO: 135 of WO2021 / 226591; SEQ ID NO: 117 and SEQ ID NO: 136 of WO2021 / 226591; SEQ ID NO: 118 and SEQ ID NO: 137; optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3 or IgG4 constant region or a variant thereof), a SIRPa binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0099] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention include those comprising the VH region set forth in SEQ ID NO: 169 and the VL region set forth in SEQ ID NO: 170 of WO2021174127; the VH region set forth in SEQ ID NO: 171 and the VL region set forth in SEQ ID NO: 172 of WO2021174127; the VH region set forth in SEQ ID NO: 173 and the VL region set forth in SEQ ID NO: 174 of WO2021174127; the VH region set forth in SEQ ID NO: 175 and the VL region set forth in SEQ ID NO: 176 of WO2021174127; the VH region shown in SEQ ID NO: 177 of WO2021174127 and the VL region shown in SEQ ID NO: 178; the VH region shown in SEQ ID NO: 179 of WO2021174127 and the VL region shown in SEQ ID NO: 180; the VH region shown in SEQ ID NO: 181 of WO2021174127 and the VL region shown in SEQ ID NO: 182; the VH region shown in SEQ ID NO: 183 of WO2021174127 and the VL region shown in SEQ ID NO: 184 or 227; the VH region shown in SEQ ID NO: 185 of WO2021174127 and the VL region shown in SEQ ID NO: 186; the VH region set forth in SEQ ID NO: 187 of WO2021174127 and the VL region set forth in SEQ ID NO: 188; the VH region set forth in SEQ ID NO: 189 of WO2021174127 and the VL region set forth in SEQ ID NO: 190; the VH region set forth in SEQ ID NO: 191 of WO2021174127 and the VL region set forth in SEQ ID NO: 192; the VH region set forth in SEQ ID NO: 193 of WO2021174127 and the VL region set forth in SEQ ID NO: 194; the VH region set forth in SEQ ID NO: 195 of WO2021174127 and the VL region set forth in SEQ ID NO: 196; the VH region set forth in SEQ ID NO: 197 of WO2021174127 and the VL region set forth in SEQ ID NO: 198; the VH region set forth in SEQ ID NO: 199 of WO2021174127 and the VL region set forth in SEQ ID NO: 200; the VH region set forth in SEQ ID NO: 201 of WO2021174127 and the VL region set forth in SEQ ID NO: 202; the VH region set forth in SEQ ID NO: 203 of WO2021174127 and the VL region set forth in SEQ ID NO: 204; the VH region set forth in SEQ ID NO: 205 of WO2021174127 and the VL region set forth in SEQ ID NO: 206;the VH region shown in SEQ ID NO: 207 of WO2021174127 and the VL region shown in SEQ ID NO: 208; the VH region shown in SEQ ID NO: 209 of WO2021174127 and the VL region shown in SEQ ID NO: 210; the VH region shown in SEQ ID NO: 211 of WO2021174127 and the VL region shown in SEQ ID NO: 212; the VH region shown in SEQ ID NO: 213 of WO2021174127 and the VL region shown in SEQ ID NO: 214; the VH region shown in SEQ ID NO: 215 of WO2021174127 and the VL region shown in SEQ ID NO: 216; the VH region shown in SEQ ID NO: 217 of WO2021174127 and the VL region shown in SEQ ID NO: 218; WO2021174 and the VH region set forth in SEQ ID NO: 219 of WO2021174127 and the VL region set forth in SEQ ID NO: 220; the VH region set forth in SEQ ID NO: 221 of WO2021174127 and the VL region set forth in SEQ ID NO: 222; or the VH region set forth in SEQ ID NO: 223 of WO2021174127 and the VL region set forth in SEQ ID NO: 224; optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region or a variant thereof), a SIRPa-binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen-binding fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer;

[0100] Additional exemplary anti-SIRPa antibodies that can be used in the disclosed invention include SEQ ID NO: 35 and SEQ ID NO: 41 of WO2019 / 226973, or SIRPa-binding portions thereof, such as antigen-binding fragments of anti-SIRPa antibodies, anti-SIRPa antibodies or antigen fragments containing the CDRs described above, which may optionally be linked to a pharmacokinetic enhancer.

[0101] Additional exemplary anti-SIRPa antibodies that can be used in the disclosed invention include SEQ ID NO: 104 and SEQ ID NO: 102 of WO2018 / 190719; or SEQ ID NO: 1 and SEQ ID NO: 2 of WO2018 / 190719, or a SIRPa-binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen-binding fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0102] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention are SEQ ID NO:64 and SEQ ID NO:78 of U.S. Patent Application Publication No. 20210347908; SEQ ID NO:65 and SEQ ID NO:79 of U.S. Patent Application Publication No. 20210347908; SEQ ID NO:65 and SEQ ID NO:80 of U.S. Patent Application Publication No. 20210347908; SEQ ID NO:66 and SEQ ID NO:81 of U.S. Patent Application Publication No. 20210347908; SEQ ID NO:65 and SEQ ID NO:82 of U.S. Patent Application Publication No. 20210347908; SEQ ID NO:67 of U.S. Patent Application Publication No. 20210347908 and SEQ ID NO: 83; SEQ ID NO: 68 and SEQ ID NO: 82 of US Patent Application Publication No. 20210347908; or SEQ ID NO: 65 and SEQ ID NO: 84 of US Patent Application Publication No. 20210347908; optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region or a variant thereof), a SIRPa binding portion of any of the above, such as an antigen-binding fragment of an anti-SIRPa antibody, an antigen fragment containing the CDRs of an anti-SIRPa antibody or any of the above, which may optionally be linked to a pharmacokinetic enhancer.

[0103] Additional exemplary anti-SIRPa antibodies that may be used in the disclosed invention include SEQ ID NO: 81 and SEQ ID NO: 64 of WO2020 / 102422; SEQ ID NO: 82 and SEQ ID NO: 65 of WO2020 / 102422; SEQ ID NO: 83 and SEQ ID NO: 66 of WO2020 / 102422; SEQ ID NO: 84 and SEQ ID NO: 67 of WO2020 / 102422; SEQ ID NO: 85 and SEQ ID NO: 68 of WO2020 / 102422; SEQ ID NO: 86 and SEQ ID NO: 69 of WO2020 / 102422; SEQ ID NO: 87 and SEQ ID NO: 70 of WO2020 / 102422; SEQ ID NO: 88 and SEQ ID NO: 71 from WO2020 / 102422; SEQ ID NO: 89 and SEQ ID NO: 72 from WO2020 / 102422; SEQ ID NO: 90 and SEQ ID NO: 73 from WO2020 / 102422; SEQ ID NO: 91 and SEQ ID NO: 74 from WO2020 / 102422; SEQ ID NO: 91 and SEQ ID NO: 75 from WO2020 / 102422; SEQ ID NO: 91 and SEQ ID NO: 76 from WO2020 / 102422; SEQ ID NO: 92 and SEQ ID NO: 74 from WO2020 / 102422; SEQ ID NO: 92 and SEQ ID NO: 75 from WO2020 / 102422; SEQ ID NO: 92 and SEQ ID NO: 76; SEQ ID NO: 93 and SEQ ID NO: 74 of WO2020 / 102422; SEQ ID NO: 93 and SEQ ID NO: 75 of WO2020 / 102422; SEQ ID NO: 93 and SEQ ID NO: 76 of WO2020 / 102422; SEQ ID NO: 94 and SEQ ID NO: 74 of WO2020 / 102422; SEQ ID NO: 94 and SEQ ID NO: 75 of WO2020 / 102422; SEQ ID NO: 94 and SEQ ID NO: 76 of WO2020 / 102422; SEQ ID NO: 84 and SEQ ID NO: 77 of WO2020 / 102422; SEQ ID NO: 95 and SEQ ID NO: 78 of WO2020 / SEQ ID NO:95 and SEQ ID NO:79 of WO2020 / 102422; SEQ ID NO:95 and SEQ ID NO:80 of WO2020 / 102422; SEQ ID NO:96 and SEQ ID NO:78 of WO2020 / 102422; SEQ ID NO:96 and SEQ ID NO:79 of WO2020 / 102422; SEQ ID NO:96 and SEQ ID NO:80 of WO2020 / 102422; SEQ ID NO:97 and SEQ ID NO:78 of WO2020 / 102422; SEQ ID NO:97 and SEQ ID NO:79 of WO2020 / 102422; SEQ ID NO:97 and SEQ ID NO:80 of WO2020 / 102422; or SEQ ID NO:89 and SEQ ID NO:72;Antibodies optionally linked to a constant region (e.g., human IgG1, IgG2, IgG3, or IgG4 constant region or variants thereof), SIRPa-binding moieties of any of the above, such as antigen-binding fragments of anti-SIRPa antibodies, antigen-binding fragments containing the CDRs of anti-SIRPa antibodies or any of the above, which may optionally be linked to a pharmacokinetic enhancer;

[0104] Additional exemplary anti-SIRPa antibodies that can be used in the disclosed invention include BR105 (Bioray Biopharmaceutical Co. Ltd.; see Clinical Trial Number NCT05351697); ELA026 (Electra Therapeutics, Inc.; see Clinical Trial Number NCT05416307); IBI397 (Innovent Biologics (Suzhou) Co. Ltd.; Alector; see Clinical Trial Number NCT05245916); BSI-050 (Biosion); BSI-082 (Biosion); ES004 (ELPIscience); APX701 (Apexigen); and BYON4228 (Byondis).

[0105] The anti-SIRPα antibodies of the present invention are disclosed in WO0066159, WO0140307, ​​WO200140307, ​​WO2009131453, WO2013056352, WO2014149477, WO2014186761, WO2015138600, WO2016063233, WO2016205042, WO2017178653, WO2018008470, WO 2018026600, WO2018057669, WO2018107058, WO2018141964, WO2018160739, WO2018190719, WO2018210793, WO201902 3347, WO2019183266, WO2019200462, WO2019226973, WO2020006374, WO2020013170, WO2020033646, WO2020068752, WO 2020102422, WO2020099653, WO2020180811, WO2020247820, WO2021022044, WO2021032078, WO2021076908, WO202112 9697, WO2021174127, WO2021185273, CN111635458, WO2021222746, WO2021226576, WO2021226591, CN113735973, CN11 1995682, CN112010979 or CN112574310, or a SIRPa-binding portion of any of the above, for example, an anti-SIRPa antibody or a CD47 fragment contained in any of the above, a SIRPa-binding fragment thereof (e.g., an antigen-binding fragment of an anti-SIRPa antibody), an anti-SIRPa antibody or an antigen fragment containing its CDRs, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0106] All of these references disclosing anti-SIRPα antibodies or antigen-binding fragments thereof are incorporated herein by reference. Any of these antibodies may be used in the same manner as the antibodies used in the experimental examples of this disclosure and according to any of the methods or uses disclosed in the present invention.

[0107] Patients who are likely to respond positively to treatment with an anti-SIRPα compound as defined herein In one embodiment of the invention there is provided a composition comprising an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating cancer in a patient, wherein the patient is - myeloid cells, in which at least 55%, in particular at least 60%, in particular at least 65.3% of the myeloid cells present in the tumor microenvironment, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, express the biomarkers CD11b and SIRPα. A composition is provided having the following structure:

[0108] In a preferred embodiment, the patient has bone marrow cells, wherein at least 55%, or at least 60%, or at least 61%, or at least 62%, or at least 63%, or at least 64%, or at least 65%, particularly at least 65.3%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of their bone marrow cells present within the tumor microenvironment, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, express the biomarkers CD11b and SIRPα. In certain embodiments, a patient has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs within the tumor microenvironment, particularly at least 55%, particularly or at least 60%, or at least 61%, or at least 62%, or at least 63%, or at least 64%, or at least 65%, particularly at least 65.3%, or at least 70%, or at least 75%, or at least 80%, or at least 95%, or at least 90% of the MDSCs express the biomarkers CD11b and SIRPα. If several types of bone marrow cells are selected for measurement of the percentage of bone marrow cells expressing CD11b and SIRPα, the percentage of cells expressing CD11b and SIRPα is measured in each type of selected bone marrow cell, and the measurements are pooled to obtain a measure of CD11b and SIRPα expression in the bone marrow cells.

[0109] Detection of bone marrow cells, including tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, expressing these markers can be performed from a biological sample previously obtained from a patient according to methods known in the art, such as immunoassays, gene expression profiles, fluorescent detection, enzyme activity assays, chemiluminescent detection, immunohistochemistry, polymerase chain reaction, reverse transcriptase polymerase chain reaction, antibody binding, receptor-binding arrays, target-specific primer extension, ELISA, and radiolabeling of SIRPα and CD11b. As an example, it is possible to measure the expression of CD11b and SIRPα on the surface of bone marrow cells present in a biological sample by immunohistochemistry or flow cytometry using several different antibodies or fluorescent dyes known to interact with one of the listed markers.

[0110] In a preferred embodiment, the patient has bone marrow cells, in particular at least 55%, particularly at least 60%, particularly at least 65.3% of whose bone marrow cells present within the tumor microenvironment, in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, express the biomarkers CD11b and SIRPα.

[0111] In one embodiment of the present invention, an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47 is administered at least once to a patient whose bone marrow cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs present within the tumor microenvironment, particularly at least 55%, particularly at least 60%, particularly at least 65.3% of the MDSCs, express SIRPα and CD11b.

[0112] In certain embodiments of the invention, there is provided a composition comprising an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, particularly between human SIRPα and human CD47, for use in treating a patient with cancer, wherein the patient: - bone marrow cells, in which at least 55%, in particular at least 60%, in particular at least 65.3%, and most preferably at least 70% of the bone marrow cells present in the tumor microenvironment, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells and / or tumor-associated neutrophils, express the biomarkers CD11b and SIRPα. A composition is provided having the following structure:

[0113] In a preferred embodiment, the patient has bone marrow cells in the tumor microenvironment. These cells can be detected in a biological sample, particularly a biopsy specimen, obtained from the patient. Cell detection can be performed by methods known in the art, such as detecting specific molecular markers associated with bone marrow cells in an IHC or flow cytometry assay.

[0114] In a preferred embodiment, the composition is for use in treating patients with SIRPα-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer, particularly cancer with solid tumors that express or overexpress SIRPα, PD-1 and / or PD-L1, wherein the patient is identified as exhibiting a biomarker disclosed by the present invention.

[0115] In a preferred embodiment, the composition is for use in the treatment of patients with solid cancer, in particular cancers with advanced solid tumours, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid gland cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer and colorectal cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, wherein the patient is identified for exhibiting a biomarker disclosed by the present invention.

[0116] A second therapeutic compound that can be administered to the patient. In some embodiments, anti-SIRPa compounds for use in the treatment methods of the invention or for use according to the invention are administered to a patient in combination with a standard or conventional or standard of care treatment. Thus, the invention relates to a combination of an anti-SIRPa compound for use in the treatment methods of the invention or for use according to the invention with a conventional treatment for use in treating cancer. As used herein, the term "standard or conventional or standard of care treatment" refers to any treatment for cancer (drugs, surgery, radiation therapy, etc.) that is typically administered to patients with cancer.

[0117] In some embodiments, an anti-SIRPα compound for use in a treatment method of the invention or for use according to the invention is administered to a patient in combination with at least one additional therapeutic agent suitable for treating cancer. Such administration may be simultaneous, separate, or sequential. For simultaneous administration, the agents may be administered as a single composition or as separate compositions, as appropriate. The additional therapeutic agent is typically related to the disorder to be treated. Exemplary therapeutic agents include other anti-cancer antibodies, cytotoxic agents, chemotherapeutic agents, anti-angiogenic agents, anti-cancer immunogens, cell cycle control / apoptosis modulating agents, hormone modulating agents, and other agents described below.

[0118] The anti-SIRPα antibody or antigen-binding fragment thereof can be administered in combination with at least one other therapeutic compound, and the anti-SIRPα antibody or antigen-binding fragment thereof can be administered in combination with several (i.e., two or more, e.g., two, three, or four) other therapeutic compounds.

[0119] In some embodiments, the anti-SIRPα compound for use in the treatment methods or for use according to the invention is used in a combination treatment with a second therapeutic agent.

[0120] The second therapeutic agent may be selected from the group consisting of chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, cellular therapy agents, antibiotics, and probiotics, and may particularly be an immunotherapeutic agent, where the immunotherapeutic agent is selected from the group consisting of immune checkpoint inhibitors or adaptive immune cell activators, and particularly selected from the group consisting of anti-PD-L1, anti-PD-1, anti-LAG-3, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1 / 3, anti-LAG-3, anti-2B4, anti-VISTA, anti-OX40, anti-CD40 agonist, CD40-L, TLR agonist, anti-ICOS, ICOS-L, STING agonist, IDO inhibitor, oncolytic virus agonist, and B cell receptor agonist, and particularly such therapeutic agent is an antibody. The drug combination is for use in the treatment of cancer.

[0121] In one embodiment, the anti-PD1 antibody is selected from the group consisting of pembrolizumab (also known as Keytruda, lambrolizumab, MK-3475), nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), pidilizumab (CT-011), cemiplimab (Libtayo), ezabenlimab (humanized programmed cell death 1 (PD-1) targeted monoclonal antibody), camrelizumab, AUNP12, AMP-224, AGEN-2034 , BGB-A317 (Tislelizumab), PDR001 (Spartalizumab), MK-3477, SCH-900475, PF-06801591, JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (HX-008), MEDI-0680 (also known as AMP-514), MEDI0608, JS001 (Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), BI-754091, CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO2014 / 194302), AGEN2034 (see WO2017 / 040790 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in WO2006 / 121168, MGA012 (see WO2017 / 19846), or IBI308 (see WO2017 / 024465, WO2017 / 025016, WO2017 / 132825 and WO2017 / 133540).

[0122] In certain embodiments of the invention, the second therapeutic agent is an anti-PD-1 antagonist or an anti-PD-L1 antagonist. In certain embodiments of the invention, the second therapeutic agent is an anti-PD-1 antibody or an anti-PD-L1 antibody, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antagonist antibody. In certain embodiments of the invention, the second therapeutic agent is a PD-1 antagonist, particularly selected from the group consisting of the following antibodies: pembrolizumab; nivolumab; pidilizumab; tislelizumab; spartalizumab; and ezabenlimab; preferably ezabenlimab. In certain embodiments of the invention, the second therapeutic agent is an anti-PD-L1 antagonist, particularly selected from the group consisting of avelumab (Bavencio), durvalumab (Imfinzi), and atezolizumab (Tecentriq).

[0123] In certain embodiments of the invention, the second therapeutic agent is administered to the patient in any therapeutically effective amount, hi certain embodiments, a therapeutically acceptable amount is from about 0.1 mg to about 50 mg per kg of patient body weight (agent / patient body weight).

[0124] In certain embodiments, the second therapeutic agent is selected from the group consisting of immune checkpoint inhibitors or activators, and in particular, the second therapeutic agent is an anti-PD-1 compound or an anti-PD-L1 compound. In preferred embodiments, the second therapeutic agent is a PD-1 antagonist compound or an anti-PD-L1 antagonist antibody. In preferred embodiments, the second therapeutic agent is an anti-PD-L1 antagonist compound, in particular an anti-PDL1 antagonist antibody, in particular avelumab (Bavencio), durvalumab (Imfinzi), or atezolizumab (Tecentriq).

[0125] The second therapeutic agent may be administered simultaneously with or separately from the anti-SIRPα antibody or antigen-binding fragment thereof, particularly subsequently or sequentially. The second therapeutic agent may be administered according to the same dosage cycle as the anti-SIRPα antibody or antigen-binding fragment thereof, simultaneously or at different times.

[0126] The present invention also relates to anti-SIRPα compounds according to any embodiment disclosed herein, in combination with a second therapeutic agent, and / or with a pharmaceutically suitable vehicle as defined herein, for use in combination therapy to treat cancer, particularly for simultaneous, separate or sequential administration to a patient in need of treatment, alone or with another treatment, including the use of a medicament comprising a chemotherapeutic agent, a radiotherapeutic agent, an immunotherapeutic agent (e.g., a tumor-targeted monoclonal antibody), a hormonal therapy agent, a cellular therapy agent (e.g., CAR-T cells), an immunosuppressant, a pro-apoptotic agent, an antibiotic, a targeted cancer therapy and / or a probiotic.

[0127] The present invention also relates to the use of anti-SIRPα compounds according to any embodiment disclosed herein, particularly for simultaneous, separate or sequential administration to a patient in need thereof and who is undergoing treatment with one of the listed therapies, alone or with another treatment including surgery, chemotherapy, radiation therapy, stem cell therapy, immunotherapy, targeted therapy, for use in combination therapy to treat cancer, in combination with a second therapeutic agent, and / or with a pharmaceutically suitable vehicle as defined herein.

[0128] Route of administration The uses and methods described herein allow for the administration of anti-SIRPα compounds by any acceptable route. In an exemplary embodiment, the pharmaceutical composition is formulated according to the route procedure as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the medicament may also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the injection site. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampule, indicating the quantity of active agent. If the medicament is to be administered by infusion, it may be dispensed in an infusion bottle containing sterile pharmaceutical-grade water or saline. If the medicament is to be administered by injection, an ampule of sterile water for injection or saline may be provided so that the ingredients can be mixed prior to administration. In some embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof is administered orally, subcutaneously, parenterally (e.g., in liquid form), rectally (i.e., in the form of a suppository), topically (e.g., in the form of a transdermal patch, ointment, or cream), or intranasally. In other words, the use of anti-SIRPα compounds and methods of using such compounds can be carried out through routes of administration including oral administration, local administration to the gastrointestinal (GI) cavity, and particularly oral administration, particularly for the treatment of cancers associated with the digestive tract. In particular, compositions suitable for systemic administration, particularly parenteral or enteral administration, and particularly intravenous injection or infusion, or oral administration are provided herein. Enteral administration can be either local administration to the digestive tract or systemic administration. Routes of administration can include the use of a device (a "delivery device") that allows for the administration of the composition, particularly injection or infusion. Examples of routes of administration may include, but are not limited to, use of the active compound as a solution, particularly a sterile aqueous solution, suspension; as a solid, particularly a lyophilized or frozen solid; adsorbed onto a patch; suspended or reconstituted and administered as a solution; or as a pill, tablet, or other solid form suitable for oral administration, particularly with delayed or extended release. Preferably, the anti-SIRPα compound is administered subcutaneously or intravenously, preferentially intravenously.

[0129] In one embodiment of the present invention, a kit is provided that includes an anti-SIRPα compound (i.e., an antibody or antigen-binding fragment thereof) for use according to any one of the embodiments disclosed herein, and a device suitable for local administration, particularly a subcutaneous or oral delivery device, particularly a device comprising a pre-filled syringe, or particularly a needle-free device. In particular, the device suitable for local administration contains the anti-SIRPα compound in a prescribed dose for direct administration to a patient without the need for dilution, completion, or reconstitution of the product prior to administration. Optionally, such a kit may be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency for manufacture, use, or sale for human administration.

[0130] ·cancer The uses and methods described herein may be useful in the treatment of cancer. In particular, the uses and methods described herein may be useful in the treatment of solid and liquid cancers. The term "cancer" has its general meaning in the art and refers to a group of diseases involving abnormal cell proliferation and the potential to invade or spread to other parts of the body. The term "cancer" encompasses both primary and metastatic cancers. Examples of cancers that can be treated by the methods and compositions of the present invention include, but are not limited to, bladder, blood, bone, bone marrow, brain, breast cancer, including triple-negative breast cancer, colon, esophagus, gastrointestinal, gingival, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterine cancer. In particular aspects of the invention, the uses and methods described herein are for the treatment of cancer in a patient, wherein the cancer is one of the following cancers: ovarian cancer, pancreatic cancer, ampulla of Vater cancer, microsatellite stable (MSS) cancer, microsatellite instability (MSI) cancer, colorectal cancer, particularly MSI and MSS colorectal cancer, fibrolamellar cancer, breast cancer, melanoma, renal cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), head and neck cancer, particularly head and neck squamous cell carcinoma (HNSCC), gastric cancer, liver cancer, endometrial cancer and hepatocellular carcinoma.

[0131] The uses described herein and the methods described herein may be useful in the treatment of cancer, where the cancer cells express antigens with low tumor specificity; for example, CD47 and PD-L1 antigens.

[0132] In certain embodiments, the uses described herein and the methods described herein may be useful in treating SIRPα, CD47, PD-L1, or PD-1-positive cancers (i.e., cancers in which tumor cells or immune cells express SIRPα, CD47, PD-L1, and / or PD-1). The patient to be treated may have been diagnosed with SIRPα-positive cancer, CD47-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer, particularly cancers involving solid tumors that express or overexpress SIRPα, CD47, PD-1, and / or PD-L1. SIRPα-, CD47-, PD-L1-, or PD-1-positive cancers are cancers in which tumor cells or immune cells express SIRPα, CD47, PD-L1, and / or PD-1. "SIRPα, CD47, PD-L1, or PD-1 positive tumor cells" refer to tumor or immune cells that express SIRPα, CD47, PD-L1, or PD-1 on their cell surface. Cancers can be classified into subsets of SIRPα, CD47, PD-L1, or PD-1 positive cancers by immunohistochemistry using monoclonal antibodies directed against SIRPα, CD47, PD-1, or PD-L1.

[0133] In a particular embodiment of the present invention, the uses and methods described herein are for the treatment of cancer in patients diagnosed with solid tumors, particularly cancers with advanced solid tumors, particularly adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, particularly ovarian cancer, breast cancer, particularly triple-negative breast cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), cervical cancer and colorectal cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer. Cancers with solid tumors may not contain any fluid or cysts. Solid tumors may correspond to either sarcomas or carcinomas.

[0134] In a particular aspect of the invention, the uses and methods described herein are for the treatment of cancer in patients with liquid or solid cancers, in particular cancers of the bladder, blood, bone, bone marrow, brain, breast cancer including triple-negative breast cancer, colon, esophagus, gastrointestinal, gingiva, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue or uterus. In a particular embodiment of the invention, the uses and methods described herein are for the treatment of cancer in a patient, wherein the cancer is one of ovarian cancer, pancreatic cancer, ampulla of Vater cancer, microsatellite stable (MSS) cancer, microsatellite instability (MSI) cancer, colorectal cancer, particularly MSI and MSS colorectal cancer, fibrolamellar cancer, breast cancer, melanoma, renal cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), head and neck cancer, particularly head and neck squamous cell carcinoma (HNSCC), gastric cancer, liver cancer, endometrial cancer and hepatocellular carcinoma, cancers positive for SIRPα, CD47, PD-L1 or PD1 as detailed herein above.

[0135] ·patient In certain embodiments of the present invention, the uses and methods described herein are for treating patients who have been previously treated for cancer and who have shown resistance to treatment and / or disease progression despite being treated. Previous treatments can include any standard, conventional cancer treatment. The term "standard or conventional treatment" refers to any cancer treatment (drugs, surgery, radiation therapy, etc.) that is typically administered to patients with cancer.

[0136] In certain aspects of the invention, the uses and methods described herein are for the treatment of patients who have been treated, are being treated, or are to be treated with an immune checkpoint inhibitor.

[0137] In particular aspects of the invention, the uses and methods described herein are for the treatment of patients who have been treated with immune checkpoint inhibitors or activators, in particular anti-PD-L1, anti-PD-1, anti-LAG-3, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1 / 3, anti-LAG-3, anti-2B4, anti-VISTA, anti-OX40, anti-CD40 agonists, CD40-L, TLR agonists, anti-ICOS, ICOS-L, STING agonists, IDO inhibitors, oncolytic virus agonists and B-cell receptor agonists, in particular anti-PD-1 or anti-PD-L1 antibodies, and who have not responded positively to administration of the immune checkpoint inhibitor or activator (i.e. the patient shows disease progression and / or does not show disease regression).

[0138] Thus, the uses and methods described herein may be for monotherapy or combination therapy for the treatment of the above-identified patients.

[0139] In certain aspects of the invention, the uses and methods described herein are for the treatment of patients who have not been, will not be, or will not be treated with an immune checkpoint inhibitor.

[0140] In certain aspects of the invention, the uses and methods described herein are for the treatment of patients who have not been treated with an anti-PD-1 or anti-PD-L1 antibody, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antagonist antibody, prior to administration of the anti-SIRPα compound.

[0141] In certain embodiments, the patient has at least one SIRPα V1 allele (i.e., is homozygous and has two SIRPα V1 alleles, or is heterozygous for SIRPα and has one SIRPα V1 allele). In certain embodiments, the patient is homozygous for SIRPα and is SIRPα V1 / SIRPα V1. In certain embodiments, the patient is heterozygous for SIRPα and is SIRPα V1 / SIRPα V2.

[0142] In certain embodiments, the patient has at least one SIRPα V2 allele (i.e., is homozygous and has two SIRPα V2 alleles, or is heterozygous for SIRPα and has one SIRPα V2 allele). In certain embodiments, the patient is homozygous for SIRPα and is SIRPα V2 / SIRPα V2.

[0143] In certain other aspects of the invention, the uses and methods described herein are carried out in combination therapy to sensitize a patient to treatment with a second therapeutic agent, particularly an immune checkpoint inhibitor or activator, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody, wherein the anti-SIRPα antibody or antigen-binding fragment thereof is administered during a first period or cycle, and the second therapeutic agent, particularly an immune checkpoint inhibitor or activator, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody, is administered during a second, subsequent period or cycle, and the second therapeutic agent, particularly an immune checkpoint inhibitor or activator, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody, is not administered during the first period or cycle.

[0144] Diagnostic and treatment methods In one embodiment, the invention provides a method for determining whether a therapy for the treatment of cancer is likely to be effective in a patient with cancer, wherein such therapy comprises an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, particularly between human SIRPα and human CD47, the method comprising: - providing a biological sample previously obtained from the patient, in particular a blood sample, a plasma sample, a serum sample, a biopsy specimen and / or a tumor sample, - determining or measuring the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, that express CD11b and SIRPα in a biological sample; Including, - if bone marrow cells expressing CD11b and SIRPα biomarkers are present in the biological sample, the patient is likely to benefit from the treatment; Regarding the method.

[0145] In certain embodiments, if the percentage of bone marrow cells expressing CD11b and SIRPα is greater than 60%, particularly greater than 65.3%, in a biological sample, the patient is likely to respond positively to treatment of their cancer by administering an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0146] In a preferred embodiment, a further step of detecting the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, particularly MDSCs, in the biological sample is carried out. The presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, particularly MDSCs, indicates that the patient is likely to respond positively to treatment of their cancer by administering a combination of: a) an anti-SIRPα antibody or an antigen-binding fragment thereof between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound that is an immune checkpoint inhibitor, for example a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, particularly an anti-PD-L1 antagonist antibody or anti-PD1 antagonist antibody, particularly an anti-PD-1 antagonist antibody, or a compound that targets lymphocyte activation gene-3 (LAG-3), particularly an antibody against lymphocyte activation gene-3. In this case, the patient is classified as likely to respond positively to treatment of their cancer by administering a combination of: a) an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound that is an immune checkpoint inhibitor, for example a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, in particular an anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, in particular an anti-PD-1 antagonist antibody, or a compound that targets lymphocyte activation gene-3 (LAG-3), in particular an antibody against lymphocyte activation gene-3.

[0147] The biological sample provided for carrying out the method is preferably a biopsy specimen derived from the tumor microenvironment. Markers expressed by myeloid cells can be detected by methods known in the art and described herein above. CD11b and SIRPα can be detected in the biological sample by a method selected from immunohistochemical analysis, immunoassay, gene expression profile, fluorescence detection, enzyme activity assay, chemiluminescence detection, polymerase chain reaction, reverse transcriptase polymerase chain reaction, antibody binding, receptor-binding array, target-specific primer extension, ELISA, and radiolabeling.

[0148] In one aspect, the present invention provides a method for treating cancer in a patient in need thereof, comprising: (a) determining that a patient has cancer presenting with a tumor microenvironment (TME) comprising myeloid cells that express both CD11b and SIRPα; (b) administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The present invention relates to a method comprising:

[0149] In a particular embodiment, the determining in step (a) above is the detection of bone marrow cells that express both CD11b and SIRPα.

[0150] In one embodiment, the present invention provides a method for treating cancer in a patient in need thereof, comprising: (a) selecting a patient with cancer whose tumor microenvironment (TME) comprises myeloid cells that express both CD11b and SIRPα; (b) administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The present invention relates to a method comprising:

[0151] In one embodiment, the present invention provides a method for treating cancer in a patient in need thereof, comprising: (a) The patient: - at least 55%, in particular at least 60%, preferably at least 65.3% of the bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; determining that the patient has cancer exhibiting one or more attributes including: (b) administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The present invention relates to a method comprising:

[0152] In a particular embodiment, the determining in step (a) above is the detection of bone marrow cells that express both CD11b and SIRPα.

[0153] In one embodiment, the present invention provides a method for treating cancer in a patient in need thereof, comprising: (a) - at least 55%, in particular at least 60%, preferably at least 65.3% of the bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα. selecting patients with cancer that exhibit one or more attributes including: (b) administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The present invention relates to a method comprising:

[0154] In the methods or uses of the present invention, which comprise administering to a patient to be treated an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, the method may comprise a final step of determining that the patient exhibits an improved outcome compared to a corresponding outcome that may be observed in a reference patient administered the anti-SIRPα antibody or antigen-binding fragment thereof, wherein the reference patient has a cancer that does not exhibit the disclosed attributes.

[0155] In one embodiment, the present invention provides a method for treating cancer in a population of cancer patients in need thereof, comprising: (a) administering to a population of cancer patients an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patients have cancer presenting with a tumor microenvironment (TME) comprising myeloid cells that express both CD11b and SIRPα; (b) observing a survival probability at 15 months in a population of cancer patients after administration of the anti-SIRPα antibody or antigen-binding fragment thereof of at least 0.45 for patients with high SIRPα expression and / or less than 0.17 for patients with low SIRPα expression; or or observing a survival probability at 10 months in a population of cancer patients after administration of the anti-SIRPα antibody or antigen-binding fragment thereof of at least 0.50 for patients with high SIRPα expression and / or less than 0.40 for patients with low SIRPα expression; or observing a survival probability at 20 months of at least 0.25 for patients with high SIRPα expression in a population of cancer patients after administration of the anti-SIRPα antibody or antigen-binding fragment thereof. The present invention relates to a method comprising:

[0156] In certain embodiments, the present invention provides a method of treating a patient in need thereof, comprising administering to the patient: - at least 55%, in particular at least 60%, preferably at least 65.3% of the bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; and determining that the individual has cancer exhibiting one or more attributes including: The method comprises administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof.

[0157] In another embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, wherein the patient has been determined to have a tumor exhibiting at least 55%, particularly at least 60%, preferably at least 65.3% of bone marrow cells present within the tumor microenvironment express the biomarkers CD11b and SIRPα; The method comprises administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof.

[0158] In another embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, wherein it has been determined that a tumor sample obtained from the patient shows that at least 55%, particularly at least 60%, preferably at least 65.3% of bone marrow cells present within the tumor microenvironment express the biomarkers CD11b and SIRPα; The method comprises administering to the patient an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof.

[0159] In another embodiment, the present invention provides a method for treating cancer in a patient in need thereof, comprising: (a) selecting a patient with a tumor showing that at least 55%, particularly at least 60%, preferably at least 65.3% of bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; and (b) administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof. The present invention relates to a method comprising:

[0160] In another embodiment, the present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) testing a sample from a cancer patient; - at least 55%, in particular at least 60%, preferably at least 65.3% of the bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; determining the presence of one or more attributes including: (b) administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof. The present invention relates to a method comprising:

[0161] In another embodiment, the present invention provides a method of treating a cancer patient, comprising administering to the cancer patient an anti-SIRPα antibody or antigen-binding fragment thereof, wherein the cancer patient: - at least 55%, in particular at least 60%, preferably at least 65.3% of the bone marrow cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; The present invention relates to a method for treating a tumor having one or more attributes including:

[0162] In another embodiment, the present invention provides a method for categorizing a human tumor, comprising: (a) testing a sample from a human to detect the presence of myeloid cells expressing the biomarkers CD11b and SIRPα within the tumor microenvironment; (b) optionally determining the presence of at least 55%, in particular at least 60%, preferably at least 65.3% of bone marrow cells expressing the biomarkers CD11b and SIRPα present within the tumor microenvironment; and (c) identifying tumors as good candidates for treatment with anti-SIRPα antibodies or antigen-binding fragments thereof; The present invention relates to a method comprising:

[0163] In any of the embodiments of the methods of treatment disclosed herein, the method can further comprise the step of formulating the anti-SIRPα antibody or antigen-binding fragment thereof for a human.

[0164] In any of the embodiments of the methods of treatment disclosed herein, the method may further comprise administering to the patient a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, more preferably an anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody.

[0165] In one embodiment of this method, the patient has been diagnosed with SIRPα-positive cancer, PD-1-positive cancer or PD-L1-positive cancer, preferably cancer involving a solid tumor that expresses or overexpresses SIRPα, PD-1 and / or PD-L1.

[0166] In any of the embodiments of the methods of treatment disclosed herein, the anti-SIRPα antibody or antigen-binding fragment thereof inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0167] In any of the embodiments of the methods of treatment disclosed herein, the anti-SIRPα antibody or antigen-binding fragment thereof is i) a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5; or SEQ ID NO:6; or SEQ ID NO:7; or SEQ ID NO:8; and ii) a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10, or i') - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 18 or SEQ ID NO: 19 or SEQ ID NO: 20 or SEQ ID NO: 21 a heavy chain variable domain comprising: ii') - a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 a light chain variable domain comprising and Preferably, the anti-SIRPα antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence shown in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence shown in SEQ ID NO:10.

[0168] In certain embodiments of any of these methods of treatment, the anti-SIRPα antibody or antigen-binding fragment thereof is i') a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 12, or ii') a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 12; iii') - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 17; and - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 21 a heavy chain variable domain comprising: - a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 a light chain variable domain comprising Includes.

[0169] In another embodiment of the methods of treatment disclosed herein, the anti-SIRPα antibody or antigen-binding fragment thereof comprises an anti-SIRPa antibody as defined herein.

[0170] In certain embodiments of the methods of treating a patient or cancer disclosed herein, the myeloid cells comprise tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils.

[0171] In one embodiment of the present invention, there is provided a method of treating a patient having a cancer that may benefit from treatment with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for a cancer involving a solid tumor, and the method comprises: - administering to a patient in need of treatment an effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47. Including, - the patient has been determined to have bone marrow cells within the patient's tumor microenvironment (TME) that express the CD11b and SIRPα biomarkers; A method is provided.

[0172] The anti-SIRPα antibody or antigen-binding fragment may correspond to any anti-SIRPα antibody or antigen-binding fragment disclosed or referenced herein, in particular: a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:10; or - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 17; and - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 21 a heavy chain variable domain comprising: - a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 or A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 12; or a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 13 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 12.

[0173] Anti-SIRPα antibodies or antigen-binding fragments are disclosed in WO2020 / 099653, WO2019 / 023347, WO2022 / 254379, WO2020 / 068752, WO2021 / 226576, WO2021174127, WO2019 / 226973, WO2018 / 190719, U.S. Patent Application Publication No. 20210347908, U.S. Patent Application Publication No. 20210347908, WO0066159, WO0140307, ​​WO20 0140307, ​​WO2009131453, WO2013056352, WO2014149477, WO2014186761, WO2015138600, WO2016063233, WO2016205042, WO20171 78653, WO2018008470, WO2018026600, WO2018057669, WO2018107058, WO2018141964, WO2018160739, WO2018190719, WO2018210 793, WO2019023347, WO2019183266, WO2019200462, WO2019226973, WO2020006374, WO2020013170, WO2020033646, WO202006875 2, WO2020102422, WO2020099653, WO2020180811, WO2020247820, WO2021022044, WO2021032078, WO2021076908, WO2021129697, It may correspond to an anti-SIRPα antibody or antigen-binding fragment disclosed in WO2021174127, WO2021185273, CN111635458, WO2021222746, WO2021226576, WO2021226591, CN113735973, CN111995682, CN112010979 or CN112574310, in particular an anti-SIRPα antibody or antigen-binding fragment disclosed in and cited in any of these publications.

[0174] In certain embodiments of the methods of treating a patient or tumor disclosed herein, the patient has at least 55%, particularly at least 60%, preferably at least 65.3% of its bone marrow cells present within the tumor microenvironment, preferably tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells and / or tumor-associated neutrophils, that express the biomarkers CD11b and SIRPα.

[0175] In certain embodiments of the methods of treating a patient or tumor disclosed herein, the patient has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils and / or MDSCs, particularly MDSCs, within the tumor microenvironment.

[0176] In certain embodiments of the methods of treating a patient or tumor disclosed herein, the patient has liquid or solid cancer, preferably cancer with an advanced solid tumor, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer and colorectal cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer.

[0177] In another embodiment, the present invention provides a method for treating cancer in a patient, wherein the patient has been diagnosed with cancer, the method comprising: - providing a biological sample previously obtained from the patient, in particular a blood sample, a plasma sample, a serum sample, a biopsy and / or a tumor sample, in particular a biological sample previously obtained from the patient, wherein the sample is a sample from the patient's tumor microenvironment (TME) and comprises bone marrow cells, in particular the sample is a biopsy of the patient's tumor microenvironment, - determining the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, that express CD11b and SIRPα in the biological sample, - administering to the patient a therapeutically effective amount of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, if the percentage of bone marrow cells that express CD11b and SIRPα is greater than 60%, particularly greater than 65.3% in the biological sample. The present invention relates to a method, comprising:

[0178] In certain embodiments, the present invention provides a method for treating cancer in a patient, wherein the patient has been diagnosed with cancer, the method comprising: - providing a biological sample previously obtained from the patient, in particular a blood sample, a plasma sample, a serum sample, a biopsy specimen and / or a tumor sample, - determining the presence of myeloid cells, in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, that express CD11b and SIRPα in the biological sample, - optionally determining the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, in particular myeloid-derived suppressor cells (MDSCs), in the biological sample, - if the percentage of myeloid cells expressing CD11b and SIRPα is greater than 65.3% in the biological sample and tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, in particular myeloid-derived suppressor cells (MDSCs), are detected in the sample, administering to the patient a combination therapy comprising: a) an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, in particular an anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, in particular an anti-PD-1 antagonist antibody. The present invention relates to a method, comprising:

[0179] In certain embodiments, the patient has cancer involving a solid tumor, particularly an advanced solid tumor. In another embodiment, the invention relates to a method for treating cancer in a patient, wherein the patient is treated for ovarian cancer, pancreatic cancer, ampulla of Vater cancer, microsatellite stable (MSS) cancer, microsatellite instability (MSI) cancer, colorectal cancer, particularly MSI and MSS colorectal cancer, fibrolamellar carcinoma, breast cancer, endocrine cancer, hepatocellular carcinoma, melanoma, renal cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), head and neck cancer, particularly head and neck squamous cell carcinoma (HNSCC), gastric cancer, and hepatocellular carcinoma.

[0180] In another embodiment, the invention relates to a method for treating cancer in a patient, wherein the patient has been diagnosed with a SIRPα-positive cancer, a PD-1-positive cancer, or a PD-L1-positive cancer, particularly a cancer involving a solid tumor that expresses or overexpresses SIRPα, PD-1, and / or PD-L1.

[0181] In another embodiment, the invention relates to a method for treating cancer in a patient who has not been previously treated with an anti-PD-L1 antibody or an anti-PD-1 antibody, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antagonist antibody.

[0182] In another embodiment, the invention relates to a method for treating cancer in a patient, wherein the patient has not been treated with an anti-SIRPα antibody prior to use.

[0183] In another embodiment, the invention relates to a method for treating cancer in a patient who has shown disease progression in response to previous treatment with an anti-PD-L1 antibody or an anti-PD-1 antibody, particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antagonist antibody.

[0184] In another embodiment, the invention relates to a method for sensitizing a patient having cancer to treatment with an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody, wherein an anti-SIRPα antibody or antigen-binding fragment thereof is administered during a first cycle, and the anti-PD-1 antagonist antibody or anti-PD-L1 antibody is administered during a second subsequent period, and the anti-PD-1 antagonist antibody or anti-PD-L1 antibody is not administered during the first period.

[0185] In another embodiment, the invention provides a method for treating cancer in a patient, comprising administering an anti-SIRPα antibody, or antigen-binding fragment thereof, to: i) a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5; or SEQ ID NO:6; or SEQ ID NO:7; or SEQ ID NO:8; and A light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10 ii) a. a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15; and b. a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and c. a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 18 or SEQ ID NO: 19 or SEQ ID NO: 20 or SEQ ID NO: 21 a heavy chain variable domain comprising: d. a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 22; and e. a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and f. a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 24 a light chain variable domain comprising and in particular, a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0186] In another embodiment, the invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody or antigen-binding fragment thereof comprising a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:10.

[0187] In another embodiment, the invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody comprising a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:8 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:10.

[0188] In another embodiment, the invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody or antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:11 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12.

[0189] In another embodiment, the invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:13 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:12. [Example]

[0190] Materials and Methods Treatment outcomes as overall survival (OS) and progression free survival (PFS) will be collected from iCRF (case report form) documentation.

[0191] Characteristics of interest, such as CD47 expression on tumor cells at baseline and SIRPα expression on CD11b+ myeloid cells, are assessed by immunohistochemistry (IHC) using Veracyte BrightPlex® technology and Leica Bond RX for sequential staining. Each tissue slide is scanned with a Nanozoomer XR / x20.

[0192] Pre-treatment samples are divided into high or low expressers based on the expression levels of these features compared to the median expression of the study population.

[0193] Kaplan-Meier curves are used to estimate survival and are calculated using Rpackage survival. The statistical test used is the log-rank test, which compares survival between high and low expresser groups. The log-rank test addresses the assumption that there is no difference between the populations studied in the likelihood of an event at any given time point, and this difference is considered significant if the p-value is less than 0.05.

[0194] Example 1 Expression of CD47, SIRPα, and CD11b on tumor and immune cells derived from the TME of patients with cancer. Patient status was assessed at baseline for biomarkers of response to anti-SIRPα antibodies or antigen-binding fragments thereof.

[0195] Figure 1 shows that categorizing patients by overall expression of CD47 on tumor cells does not distinguish patients who benefit from treatment with an anti-SIRPα antibody in terms of overall survival from patients who do not benefit from treatment despite being treated with the same antibody. Whether a patient is treated with anti-SIRPα antibody monotherapy or combination therapy of an anti-SIRPα antibody with a PD1 inhibitor, assessing CD47 expression on tumor cells is not suitable for assessing whether a patient is likely to benefit from treatment with an anti-SIRPα antibody alone or in combination, particularly in combination with a PD1 inhibitor.

[0196] Figure 2 shows that categorizing patients by overall expression of SIRPα on tumor cells does not distinguish patients who benefit from treatment with an anti-SIRPα antibody in terms of overall survival from patients who do not benefit from treatment despite being treated with the same antibody. Whether a patient is treated with anti-SIRPα antibody monotherapy or combination therapy of an anti-SIRPα antibody with a PD1 inhibitor, assessing CD47 expression on tumor cells is not suitable for assessing whether a patient is likely to benefit from treatment with an anti-SIRPα antibody alone or in combination, particularly in combination with a PD1 inhibitor.

[0197] Figure 3 shows that categorizing patients according to the presence of CD11b+SIRPα+ bone marrow cells in the tumor microenvironment can distinguish patients who benefit from treatment with an anti-SIRPα antibody (i.e., their disease regresses, does not progress, or progresses more slowly) from patients who do not benefit from treatment despite being treated with the same antibody. As shown in Figures 3A and 3B, patients with at least 65.3% CD11b+SIRPα+ bone marrow cells survive longer than patients with less than 65.3% CD11b+SIRPα+ bone marrow cells: after 30 months of treatment, 25% of patients with at least 65.3% CD11b+SIRPα+ bone marrow cells are still alive. This patient categorization is valid when patients are treated with anti-SIRPα antibody monotherapy and when patients are treated with anti-SIRPα antibody combination therapy, especially in combination with a PD1 inhibitor.

[0198] Figures 3C, 3D, 3E, and 3F show that patients with at least 60% (Figures 3C and 3D) or 55% (Figures 3E and 3F) of CD11b+SIRPα+ bone marrow cells survive longer than patients with less than 60% or 55% CD11b+SIRPα+ bone marrow cells: after 20 months of treatment, 25% of patients with at least 60% or 55% CD11b+SIRPα+ bone marrow cells are still alive. This patient classification is valid when patients are treated with anti-SIRPα antibody monotherapy and when patients are treated with anti-SIRPα antibody combination therapy, especially in combination with PD1 inhibitors. In patients treated with anti-SIRPα antibody monotherapy or combination therapy, the overall survival curves of patients with more than 65.3% CD11b+SIRPα+ bone marrow cells decrease more slowly than those of patients with more than 60% or 55% CD11b+SIRPα+ bone marrow cells. After 20 months of treatment, the overall survival of patients with over 65.3% CD11b+SIRPα+ bone marrow cells is higher than that of patients with lower percentages of CD11b+α+ bone marrow cells.

[0199] Furthermore, the overall survival curves of patients with more than 65.3% CD11b+SIRPα+ bone marrow cells decrease more slowly than those of patients with less than 60% CD11b+SIRPα+ bone marrow cells.

[0200] Figure 4 shows that the gene expression profiles of immune cells present in the tumor microenvironment of patients who were treated with a combination of an anti-SIRPα antibody and a PD1 inhibitor and who responded positively to this treatment were similar to those of MDSCs. Thus, these results indicate that the presence of MDSCs in the tumor microenvironment is a potential predictive marker for the efficacy of combination therapy with an anti-SIRPα antibody and a PD1 inhibitor.

[0201] The predictive results are particularly beneficial for combination therapies that involve administration of both anti-SIRPα antibodies and anti-PD1.

Claims

1. A composition comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating cancer in a patient, wherein the cancer is characterized by a tumor whose tumor microenvironment (TME) comprises bone marrow cells that express both CD11b and SIRPα, and the patient has at least 55%, particularly at least 60%, particularly at least 65.3% of its bone marrow cells present in the TME before and / or during the treatment that express CD11b and SIRPα.

2. The composition for use of claim 1, wherein the bone marrow cells from the TME are derived from a biological sample previously obtained from the TME of the patient.

3. 3. The composition for use according to claim 1 or 2, wherein the microenvironment of the tumor of the patient comprises tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, in particular MDSCs, expressing the biomarkers CD11b and SIRPα.

4. 3. The composition for use of claim 1 or 2, wherein the patient has bone marrow cells within the microenvironment of the tumor.

5. 5. The composition for use according to any one of claims 1 to 4 for the treatment of patients with liquid or solid cancer, in particular cancer with advanced solid tumours, in particular adrenal cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer and colorectal cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer.

6. Immune checkpoint inhibitors of the interaction between tumor cells and myeloid cells, particularly anti-PD-L1, anti-PD-1, anti-LAG-3, anti-CTLA4, anti-CD137, anti-CD2, anti-CD28, anti-CD40, anti-HVEM, anti-BTLA, anti-CD160, anti-TIGIT, anti-TIM-1 / 3, anti-LAG-3, anti-2B4, anti-VISTA, anti-OX40, anti-CD40 agonists, CD40-L, TLR agonists, anti-ICOS, ICOS-L, STING agonists, IDO inhibitors, oncolytic virus agonists and B cell receptor agonists 6. The composition for use according to any one of claims 1 to 5, to be administered in combination treatment with a compound selected from the group consisting of agonists, particularly a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, particularly an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody, or with a compound that targets lymphocyte activation gene-3 (LAG-3), particularly an antibody against lymphocyte activation gene-3.

7. 7. The composition for use according to claim 5 or 6, wherein the patient has been diagnosed with SIRPα-positive cancer, PD-1-positive cancer or PD-L1-positive cancer, preferably cancer with a solid tumor that expresses or overexpresses SIRPα, PD-1 and / or PD-L1.

8. The composition for use according to any one of claims 1 to 7, wherein CD11b and SIRPα are measured by immunohistochemistry (IHC).

9. the anti-SIRPα antibody or antigen-binding fragment thereof, a. a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5; or SEQ ID NO:6; or SEQ ID NO:7; or SEQ ID NO:8; and b. A light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10 Including, The composition for use according to any one of claims 1 to 8, wherein the anti-SIRPα antibody or antigen-binding fragment thereof preferably comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:

10.

10. i') a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 12, or ii') a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 13, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 12 10. The composition for use according to any one of claims 1 to 9, comprising an anti-SIRPα antibody comprising:

11. 1. A method for assessing a patient's status for biomarkers of response to treatment with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for cancer involving a liquid tumor or a solid tumor, the method comprising: - providing a biological sample previously obtained from said patient, said sample being a sample from the tumor microenvironment (TME) of said patient and comprising bone marrow cells, in particular said sample being a biopsy specimen of said microenvironment of said patient's tumor, - determining the presence in said biological sample of myeloid cells that express CD11b and SIRPα biomarkers. A method comprising:

12. 1. A method for determining whether a patient having cancer is likely to benefit from treatment with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for cancer involving a solid tumor, the method comprising: - providing a biological sample previously obtained from said patient, said sample being a sample from the tumor microenvironment (TME) of said patient and comprising bone marrow cells, in particular said sample being a biopsy specimen of said microenvironment of said patient's tumor, - determining the presence in said biological sample of myeloid cells that express CD11b and SIRPα biomarkers. Including, - if bone marrow cells expressing CD11b and SIRPα biomarkers are present in the biological sample, then the patient is likely to benefit from the treatment; method.

13. The method of claim 11 or 12, wherein the patient is likely to respond positively to cancer treatment by administering an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits binding between SIRPα and CD47, preferably between human SIRPα and human CD47, if the percentage of bone marrow cells that express CD11b and SIRPα is at least 55%, particularly at least 60% in the biological sample.

14. 14. The method according to any one of claims 11 to 13, wherein the patient has liquid or solid cancer, in particular cancer with advanced solid tumours, in particular adrenal gland cancer, biliary tract cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, pancreatic cancer, parotid gland cancer, prostate cancer or uterine cancer, in particular ovarian cancer, breast cancer, in particular triple-negative breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), cervical cancer and colorectal cancer, especially non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer.

15. 15. The method of any one of claims 11 to 14, further comprising the step of detecting the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, in particular MDSCs, in the biological sample, wherein the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, in particular MDSCs, indicates that the patient is likely to respond positively to treatment of their cancer by administering a combination of: a) an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound that is an immune checkpoint inhibitor, in particular a compound that inhibits the binding between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1, in particular an anti-PD-L1 antagonist antibody or anti-PD1 antagonist antibody, in particular an anti-PD-1 antagonist antibody, or a compound that targets lymphocyte activation gene-3 (LAG-3), in particular an antibody against lymphocyte activation gene-3.

16. 16. The method of any one of claims 11 to 15, wherein the patient is likely to respond positively to treatment of their cancer by administering a combination of: a) an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, particularly between human SIRPα and human CD47, and b) a compound that inhibits the binding between PD-1 and PDL-1, preferably between human PD-1 and human PD-L1, particularly an anti-PD-L1 antagonist antibody or an anti-PD1 antagonist antibody, particularly an anti-PD-1 antagonist antibody, or a compound that targets lymphocyte activation gene-3 (LAG-3), particularly an antibody against lymphocyte activation gene-3.

17. 17. The method according to any one of claims 11 to 16, wherein CD11b and SIRPα are detected in a biological sample by a method selected from immunoassays, in particular immunohistochemistry, gene expression profiling, fluorescence detection, enzyme activity assays, chemiluminescence detection, polymerase chain reaction, reverse transcriptase polymerase chain reaction, antibody binding, receptor-binding arrays, target-specific primer extension, ELISA, and radiolabeling.

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