Therapeutic predictive biomarkers for anti-SIRPa antibodies

Abstract

The present application relates generally to the treatment of cancer patients exhibiting immune cells (particularly myeloid cells, such as tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSC and / or tumor-associated neutrophils) expression biomarkers CD11b and SIRP alpha in the tumor microenvironment. These patients have been recognized as best responders to therapies comprising administration of anti-SIRP alpha antagonist antibodies.

Description

Technical Field

[0001] The present application generally relates to the treatment of cancer patients using anti-SIRPα antibodies or antigen-binding fragments thereof. In particular, the present invention relates to the use and methods of treating patients who are more likely to respond positively to cancer treatment using anti-SIRPα antagonist antibodies or antigen-binding fragments thereof, wherein the cancer treatment is carried out by administering an anti-SIRPα antibody or antigen-binding fragment thereof alone, or in combination with other therapeutic compounds (such as other antibodies), therapeutic methods (such as radiotherapy or chemotherapy), or so-called standard-of-care treatments (i.e., the therapies that are generally recommended for treating a patient's cancer).

[0002] Accordingly, the present application relates to the treatment of cancer patients in which immune cells (especially myeloid cells, especially tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or myeloid-derived suppressor cells (MDSCs), more particularly MDSCs) in the tumor microenvironment express the biomarkers CD11b and SIRPα. According to the present invention, these patients have been identified as patients who are most responsive to therapies including the administration of anti-SIRPα antagonist antibodies. More particularly, the present invention is directed to measuring the expression of these specific markers by immune cells (especially myeloid cells, such as tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs) obtained from cancer patients, and administering an anti-SIRPα antibody or antigen-binding fragment thereof alone or in combination to patients with cells expressing the specific markers. Background Art

[0003] Cancer is a major global health problem, causing approximately 9.5 million deaths per year, while more than 20 million people are diagnosed with cancer each year (World Health Organization World Cancer Report, 2018). Immune checkpoints targeting adaptive immunity have proven to have excellent therapeutic efficacy against a variety of cancers. Research on immune checkpoints on myeloid cells (such as macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and polymorphonuclear leukocytes or neutrophils (PMNs)) is not yet sufficient, while these cells are abundant immune cell types in many solid tumors and are generally associated with poor prognosis. Signal regulatory protein α (SIRPα, also known as SIRP-α, SIRPα, CD172a, or SHPS-1) is expressed on monocytes, most tissue macrophage subsets, MDSCs, granulocytes, dendritic cell subsets in lymphoid tissues, some bone marrow progenitors, and is expressed at different levels on neurons, with prominent expression in synapse-rich regions of the brain, such as the granular layers of the cerebellum and hippocampus.

[0004] SIRPα is a prototype member of the SIRP paired receptor family, which consists of closely related SIRP proteins, including SIRPα, SIRPg (also known as SIRP-γ, SIRPγ, CD172g or SIRPβ-2), and SIRPb (also known as SIRP-β, SIRPβ, CD172b). Signal regulatory protein (SIRP) constitutes a family of cell surface glycoproteins that are expressed on myeloid cells (including macrophages, granulocytes, myeloid dendritic cells, and mast cells), neuronal cells (summarized in "Barclay, A.N. & Brown, M.H., Nat Rev Immunol 6, 457-64 (2006)"; see also WO97 / 48723), as well as some normal tissue cells and tumor cells. CD47 is a widely expressed transmembrane glycoprotein that functions as a cellular binding ligand for SIRPα and binds to the NH2-terminal extracellular domain of SIRPα. The most well-documented role of SIRPα is its inhibitory effect in the process of macrophage phagocytosis of host cells. In particular, SIRPα on macrophages binds to CD47 expressed on target cells, generating an inhibitory signal that negatively regulates phagocytosis. However, more recent studies have also demonstrated other positive signaling effects mediated by SIRPα binding (Shultz, L.D. et al., (1995) J Immunol 154, 180-91).

[0005] SIRPα expressed by myeloid cells interacts with the ubiquitously expressed receptor CD47, and this interaction is an important immune checkpoint in the innate response and is involved in the regulation of myeloid function. The interaction between SIRPα and CD47 provides a downregulatory signal that inhibits phagocytosis of host cells. Since CD47 is widely overexpressed in some cancer cells, CD47 acts as a "don't eat me" signal in some tumors containing these cells, thus avoiding being phagocytosed. In recent years, the potential role of the CD47-SIRPα interaction in cancer cell clearance has been intensively studied. Studies have shown that the abundance of CD47 receptors in tumors is negatively correlated with the overall survival of patients and is an adverse prognostic factor for multiple cancer types.

[0006] Accordingly, a variety of drugs have been developed targeting the SIRPα / CD47 pathway to enhance macrophage phagocytosis. These include the use of fragmented / truncated SIRPα and / or CD47 proteins and their antibodies. Cancer cells overexpress CD47, rendering them resistant to macrophages, even when these cells are coated with therapeutic antibodies. Blocking the SIRPα / CD47 pathway with drugs targeting CD47 has been shown to enhance antibody-dependent phagocytosis by macrophages. These therapies have also been described as having a synergistic effect with depleting therapeutic anti-cancer antibodies (such as Trastuzumab (anti-Her2), Cetuximab (anti-EGFR), Rituximab (anti-CD20), and Alemtuzumab (anti-CD52)).

[0007] Accordingly, anti-human SIRPα antibodies that can disrupt the binding of SIRPα to CD47 have been developed in recent years. However, there is still a need to improve the application of these antibodies, particularly to adjust their in vivo effects, such as by enhancing the patient's response to the anti-SIRPα antibody or its antigen-binding fragment. There is also a need to improve the combined use of these compounds with existing treatments or existing therapies.

[0008] In this context, it is crucial for patients to be able to determine in a reliable manner the likelihood of a positive response to treatment in a specific patient, more particularly a patient receiving anti-cancer treatment. In particular, it is necessary to evaluate whether the intended treatment for a cancer patient can effectively treat the disease. WO2014 / 186761 describes gene biomarkers related to the response to anti-CD47 drugs, particularly anti-SIRPα antibodies, and indicates that the SPP1, CHITl, FCyR2A, and FCyR3A genes are putative markers of this response. WO2020 / 107115 describes biomarkers for CD47 cancer treatment. The identified markers are secreted proteins or cellular immunoreceptors (monocyte chemoattractant protein 3 (MCP-3), monocyte chemoattractant protein 1 (MCP-1), interleukin-1α (IL-1A), interleukin 8 (IL-8), macrophage inflammatory protein 1-α (MIP-1α), macrophage inflammatory protein 1-β (MIP-1β), monokine induced by gamma interferon (MIG)). These biomarkers are not related to the effectiveness of cancer treatment. In addition, the biomarkers described in the above-cited applications are not efficacy-predictive biomarkers. These biomarkers represent the binding of drug targets and their correlation with clinical responses.

[0009] Typically, when seeking biomarkers for immunotherapy, those skilled in the art measure the expression of target molecules on tumors to evaluate the potential efficacy of antibodies targeting those molecules. Thus, those skilled in the art measure the expression level of CD47 (since it is a molecule expressed by tumor cells) to evaluate whether the use of an anti-SIRPα antibody might be beneficial to patients receiving treatment with that antibody. The inventors have demonstrated that the expression of CD47 in tumor cells is highly heterogeneous.

[0010] The Applicant has now demonstrated that heterogeneous expression of CD47 in tumor cells is observed in patients with progressive disease. In addition, CD47 has different ligands that are also involved in tumorigenesis. Thus, when treatment is based on the use of an anti-SIRPα antibody or its antigen-binding fragment, CD47 does not constitute a reliable predictive biomarker for treating cancer patients in need. SUMMARY OF THE INVENTION

[0011] The inventors have developed a new method that includes evaluating a patient's status with respect to a biomarker that has predictive value related to the benefit of cancer treatment comprising an anti-SIRPα antibody or its antigen-binding fragment, wherein the evaluation is not based on the consequences of blocking the CD47 / SIRPα axis, but rather on the expression level of specific immune cells (i.e., based on CD11b+ / SIRPα+ myeloid cells in the tumor microenvironment), such as the expression level in tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly in MDSCs).

[0012] At baseline (baseline = before treatment with an anti-SIRPα antibody), the level of CD11b+ myeloid cells expressing SIRPα is higher in patients with stable disease and partial remission compared to patients with disease progression. A high level of CD11b+ myeloid cells expressing SIRPα is a driver of better overall survival, rather than CD47.

[0013] As shown in the present application, the level of CD11b+ myeloid cells expressing SIRPα in a patient's tumor microenvironment (TME) is associated with better overall survival (OS) and corresponding drug efficacy. Thus, the level of CD11b+ / SIRPα+ myeloid cells is provided as a key predictive biomarker for whether a patient is suitable for treatment with an anti-SIRPα antibody or its antigen-binding fragment. The Applicant has demonstrated that the level of CD11b+ myeloid cells expressing SIRPα in the TME will determine drug efficacy.

[0014] In summary, compared with CD47 expression on tumor cells, CD11b+ myeloid cells that also express SIRPα in the tumor microenvironment are more relevant to identifying patients who are more likely to benefit from anti-SIRPα antibodies or antigen-binding fragments thereof. Additionally, the potential of anti-SIRPα antibodies or antigen-binding fragments thereof is most relevant to SIRPα expression on CD11b+ myeloid cells. Meanwhile, no association was found between SIRPα expression on tumor cells and better overall survival (OS) and corresponding drug efficacy.

[0015] Accordingly, the present invention provides new uses and methods for treating cancer patients, including administering an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof. In other words, the present invention provides the use of an anti-SIRPα compound, particularly an anti-SIRPα antibody and antigen-binding fragment thereof, and a method of administering such a compound to a cancer patient when the patient has been demonstrated to be likely to benefit from or respond positively to such treatment.

[0016] The inventors herein provide the use and method of administration of an anti-SIRPα compound, particularly an anti-SIRPα antibody and antigen-binding fragment thereof, as a single therapy or in combination therapy (simultaneously, subsequently, or as an initial therapy) with other therapeutic agents (such as but not limited to immunotherapeutic agents, such as immune checkpoint inhibitors or activators) and / or therapeutic methods (such as but not limited to surgery, radiotherapy, chemotherapy, hormonal therapy).

[0017] As detailed in this application, at least two significant advancements have been made. In a first aspect, the inventors of the present invention have found that when an anti-SIRPα drug, particularly an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between CD47 and SIRPα, is administered, patients diagnosed with cancer and whose tumor microenvironment (TME) contains myeloid cells expressing CD11b and SIRPα are more likely to benefit from their cancer treatment. For example, compared to what would be expected without treatment, the overall survival of the patients is improved, or the patients have a positive response to their cancer treatment.

[0018] According to a particular embodiment, patients diagnosed with cancer in which at least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells in the tumor microenvironment express the biomarkers CD11b and SIRPα are more likely to have a positive response to treatment of their cancer by administration of an anti-SIRPα agent, particularly an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between CD47 and SIRPα. While it was previously thought that CD47 should be measured to assess whether a therapy based on inhibition of the CD47-SIRPα interaction was likely to be successful (since CD47 is typically expressed by tumor cells), the inventors have shown in the first aspect of the present invention that overall survival is correlated with SIRPα expression in myeloid cells expressing CD11b (p value < 0.05).

[0019] The levels of myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, more particularly MDSCs) expressing the biomarkers of the present invention represent the results of measurements by immunohistochemistry. Other methods for characterizing the markers of cell expression can also be used to measure the levels of myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, more particularly MDSCs) expressing the biomarkers of the present invention.

[0020] Typically, determining whether a cancer therapy is likely to be successful requires determining or measuring biomarker expression in the patient's tumor cells (rather than myeloid cells). The inventors have found that positive clinical outcomes or responses are observed in patients having at least 55% (particularly at least 60%, particularly at least 65.3%) of CD11b-positive and SIRPα-positive myeloid cells compared to patients having less than 60% (particularly less than 65.3%) of CD11b-positive and SIRPα-positive myeloid cells. The percentage of myeloid cells expressing CD11b and SIRPα is correlated with better overall survival (OS) and better efficacy of treatment in patients receiving anti-SIRPα antagonist antibody therapy (monotherapy or combination therapy). Thus, CD11b-positive and SIRPα-positive myeloid cells (also referred to as CD11+ / SIRPα+ myeloid cells) are key predictive biomarkers for selecting or targeting patients who may benefit from a therapy comprising administration of an anti-SIRPα antagonist antibody or antigen-binding fragment thereof.

[0021] In a particular embodiment, myeloid cells expressing CD11b and SIRPα in the tumor microenvironment (TME) are measured before treatment of a patient, particularly before administration to the patient of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47. Then, the measured value of myeloid cells expressing CD11b and SIRPα in the tumor microenvironment (TME) before treatment is considered the baseline level of CD11b+, SIRPα+ myeloid cells.

[0022] In a particular embodiment, myeloid cells expressing CD11b and SIRPα in the TME are measured during treatment of a patient, particularly during administration to the patient of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47. Then, the measured value of myeloid cells expressing CD11b and SIRPα in the tumor microenvironment (TME) during treatment is considered the baseline level of CD11b+, SIRPα+ myeloid cells. During a treatment regimen that involves multiple administrations (at least two), the measurement is made at the same time as or after the first administration and before the last scheduled administration.

[0023] There is provided a composition comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits the binding between SIRPα and CD47, preferably human SIRPα and human CD47, for use in treating cancer in a patient, wherein the cancer is characterized by a tumor in which the tumor microenvironment (TME) comprises myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, more particularly MDSCs) expressing CD11b and SIRPα.

[0024] In a particular embodiment, there is provided a composition comprising an anti-SIRPα compound, particularly an anti-SIRPα antibody or antigen-binding fragment thereof, that inhibits the binding between SIRPα and CD47, preferably human SIRPα and human CD47, for use in treating cancer in a patient, wherein the cancer is characterized by a tumor in which the tumor microenvironment (TME) comprises tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs expressing CD11b and SIRPα. Each of the tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs can be considered a subset of myeloid cells.

[0025] In a particular embodiment, the use of a composition for treating cancer in a patient, wherein the cancer is characterized by: when detected by immunohistochemistry (IHC), 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, more particularly MDSCs) in the tumor microenvironment (TME) express the biomarkers CD11b and SIRPα.

[0026] In another embodiment of the use, the patient's tumor microenvironment contains tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs that express the biomarkers CD11b and SIRPα.

[0027] In another embodiment of the use, the patient's tumor microenvironment contains tumor-associated macrophages that express the biomarkers CD11b and SIRPα.

[0028] In another embodiment of the use, the patient's tumor microenvironment contains monocytes that express the biomarkers CD11b and SIRPα.

[0029] In another embodiment of the use, the patient's tumor microenvironment contains myeloid dendritic cells that express the biomarkers CD11b and SIRPα.

[0030] In another embodiment of the use, the patient's tumor microenvironment contains tumor-associated neutrophils that express the biomarkers CD11b and SIRPα.

[0031] In another embodiment of the use, the patient's tumor microenvironment contains tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and MDSCs that express the biomarkers CD11b and SIRPα.

[0032] In a particular embodiment, the patient's tumor microenvironment has myeloid cells, which include tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly MDSCs.

[0033] In a particular embodiment, a composition is provided that contains an anti-SIRPα compound, particularly an anti-SIRPα antibody or an antigen-binding fragment thereof, that inhibits the binding between SIRPα and CD47, preferably inhibits the binding between human SIRPα and human CD47, for use in treating a patient suffering from cancer, the patient having:

[0034] - At least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs) present in the tumor microenvironment express the biomarkers CD11b and SIRPα. Accordingly, the present invention also relates to a composition comprising an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably inhibits the binding between human SIRPα and human CD47, for use in a method of treating cancer in a cancer patient, wherein the method comprises:

[0035] - Measuring myeloid cells expressing CD11b and SIRPα present in a biological sample obtained from the patient, particularly tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils, wherein the myeloid cells are from the tumor microenvironment,

[0036] - When at least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells (particularly tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils) present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0037] - Administering a treatment comprising an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0038] In a particular embodiment, the composition for use according to the invention as disclosed in the various embodiments is for the treatment of liquid cancer or solid cancer, particularly cancer with advanced solid tumors, more particularly adrenocortical carcinoma, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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; more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (particularly non-small cell lung cancer (NSCLC)), cervical cancer, or colorectal cancer, most particularly ovarian cancer, colorectal cancer, or non-small cell lung cancer (NSCLC).

[0039] In a third aspect of the present invention, the inventors have found that the presence or absence of specific immune cells with the identified predictive biomarkers disclosed herein in the tumor microenvironment of a patient is respectively associated with a clinical benefit, particularly with a positive or negative response of the patient to treatment of cancer with an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47 (particularly in combination with a second therapeutic agent).

[0040] Accordingly, there is provided a composition comprising an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in combination therapy with an immune checkpoint inhibitor for the interaction between tumor cells and myeloid cells, particularly for use in combination therapy with a compound that inhibits the interaction between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1 (such as a therapeutic agent selected from an anti-PD-1 or anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody), or for use in combination therapy with a compound that targets lymphocyte activation gene-3 (LAG-3) (particularly an antibody against lymphocyte activation gene-3), the composition for simultaneous or sequential administration, the composition for use in treating a patient having cancer and who is likely to respond positively to the treatment as detected according to the present invention.

[0041] In a particular embodiment, the patient's tumor microenvironment has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs.

[0042] In a particular embodiment, the patient's tumor microenvironment has tumor-associated macrophages.

[0043] In a particular embodiment, the patient's tumor microenvironment has monocytes.

[0044] In a particular embodiment, the patient's tumor microenvironment has myeloid dendritic cells.

[0045] In a particular embodiment, the patient's tumor microenvironment has tumor-associated neutrophils.

[0046] In a particular embodiment, the patient's tumor microenvironment has MDSCs.

[0047] In a particular embodiment, the patient's tumor microenvironment has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and MDSCs.

[0048] Administration of an anti-SIRPα antibody can lead to increased expression of PD-1 and / or PD-L1 in tumors. Thus, the combination 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 resistant to monotherapy. The anti-SIRPα antibody can enhance the anti-tumor effect of an anti-PD-L1 antibody or an anti-PD-1 antibody, particularly in patients in whom the CD11b and SIRPα biomarkers of the present invention are positive in the tumor microenvironment and in whom the tumor microenvironment optionally has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly MDSCs).

[0049] Use of an anti-SIRPα antibody or an antigen-binding fragment thereof as disclosed herein enhances the presence of immune cells in the tumor microenvironment. Administration of an anti-SIRPα antibody or an antigen-binding fragment thereof can increase the expression of a specific biomarker (e.g., PD-L1), thereby enhancing the efficacy of other therapies in combination with an anti-SIRPα drug. The inventors have demonstrated that such combinations of therapeutic agents are particularly effective in patients having tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly MDSCs) in the tumor microenvironment.

[0050] According to one aspect of the present invention, there is provided a method for assessing the status of a biomarker of a patient's responsiveness to treatment with an anti-SIRPα antibody or an antigen-binding fragment thereof, which anti-SIRPα antibody or antigen-binding fragment inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for cancer having a solid tumor, the method comprising:

[0051] - providing a biological sample previously obtained from the patient, wherein the sample is from the patient's tumor microenvironment (TME) and contains myeloid cells, particularly, the sample is a biopsy sample of the patient's tumor microenvironment;

[0052] - determining the presence of myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and MDSCs expressing the CD11b and SIRPα biomarkers, more particularly MDSCs expressing the CD11b and SIRPα biomarkers) in the biological sample that express the CD11b and SIRPα biomarkers.

[0053] According to a specific embodiment, there is also provided a method for determining whether a cancer patient is likely to benefit from a therapy for treating cancer, the method comprising:

[0054] - Provide a biological sample previously obtained from a patient, wherein the sample is from the patient's tumor microenvironment (TME) and contains myeloid cells. In particular, the sample is a biopsy sample of the patient's tumor microenvironment;

[0055] - Determine or measure 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 the biological sample;

[0056] - If myeloid cells expressing the CD11b and SIRPα biomarkers are present in the biological sample (in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs), the patient may benefit from the treatment.

[0057] In a particular embodiment, when the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample is at least 55%, in particular at least 60%, in particular at least 65.3%, the patient is classified as likely to have a positive response to treatment of their cancer by administration of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0058] According to a particular embodiment, there is also provided a method of differentiating cancer patients, i.e., a method of differentiating cancer patients who are likely to have a positive response to their cancer treatment from those who do not have a positive response to their cancer treatment, wherein the cancer treatment is by administration of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, the method comprising:

[0059] - Provide a biological sample previously obtained from a patient, wherein the sample is from the patient's tumor (TME) microenvironment and contains myeloid cells. In particular, the sample is a biopsy sample of the patient's tumor microenvironment;

[0060] - Determine or measure the presence of myeloid cells (in particular tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and tumor-associated neutrophils) expressing CD11b and SIRPα in the biological sample;

[0061] - If myeloid cells expressing the CD11b and SIRPα biomarkers are present in the biological sample, the patient may benefit from the treatment, and / or the patient may have a positive response to the treatment.

[0062] In a particular embodiment, the patient who may respond positively to treatment is a patient in whom at least 55%, particularly at least 60%, particularly 65.3% of the myeloid cells in their biological sample express CD11b and SIRPα.

[0063] According to a particular embodiment, there is also provided a method of treating cancer in a cancer patient, the method comprising:

[0064] - providing a biological sample previously obtained from the patient, wherein the sample is from the patient's tumor microenvironment (TME) and contains myeloid cells, particularly, the sample is a biopsy sample of the patient's tumor microenvironment;

[0065] - measuring the presence of myeloid cells (particularly tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils) expressing CD11b and SIRPα in the biological sample;

[0066] - when myeloid cells expressing the CD11b and SIRPα biomarkers are present in the biological sample, administering to the patient alone or in combination therapy an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, said combination therapy being in combination with an immune checkpoint inhibitor that inhibits the interaction between tumor cells and myeloid cells, particularly in combination with a compound that inhibits the interaction between PD-1 and PD-L1, preferably between human PD-1 and human PD-L1 (such as a therapeutic agent selected from anti-PD-1 or anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies, more preferably an anti-PD-1 antagonist antibody), or in combination with a compound that targets lymphocyte activation gene-3 (LAG-3) (particularly an antibody against lymphocyte activation gene-3).

[0067] In a particular embodiment of the method, the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample is at least 55%, particularly at least 60%, particularly at least 65.3%.

[0068] In a particular embodiment of the method of treating cancer, an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, is administered to the patient in combination therapy with a second therapeutic agent (particularly an anti-PD-1 or anti-PD-L1 antibody).

[0069] In a specific embodiment of the treatment method, the patient has a liquid or solid cancer, particularly a cancer with advanced solid tumors, more particularly adrenal cancer, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (particularly non-small cell lung cancer (NSCLC)), cervical cancer or colorectal cancer, and most particularly ovarian cancer, colorectal cancer or non-small cell lung cancer (NSCLC).

[0070] According to a specific embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of the following cancers: cancers with solid tumors, more particularly cancers with advanced solid tumors, more particularly adrenal cancer, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (particularly non-small cell lung cancer (NSCLC)), cervical cancer or colorectal cancer, wherein the patient is identified as exhibiting the biomarker disclosed by the present invention.

[0071] According to a specific embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the combined treatment of cancer with an immune checkpoint inhibitor or activator, wherein the patient is identified as exhibiting the predictive biomarker disclosed by the present invention.

[0072] According to a specific embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of a patient who is known or has been proven to be non-responsive to cancer treatment or therapy before this application and / or still exhibits cancer disease progression despite ongoing treatment. According to this embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of cancer in a patient who has failed treatment with at least one alternative cancer treatment agent or treatment method, wherein the patient is identified as exhibiting the predictive biomarker disclosed by the present invention.

[0073] According to a specific embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of a patient who has not been treated before this application. According to this embodiment, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for the treatment of cancer in a patient as a first-line therapy.

[0074] According to certain embodiments, the present invention provides the use of an anti-SIRPα antibody or an antigen-binding fragment thereof for treating a patient who has been treated with an immune checkpoint inhibitor or activator (in particular an anti-PD-1 or anti-PD-L1 drug) and has not had a positive response or has not maintained a response to the administration of the immune checkpoint inhibitor or activator (i.e., the patient exhibits disease progression and / or does not exhibit disease regression), wherein the patient is identified as exhibiting a biomarker disclosed in the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 There is no correlation shown between the overall survival of patients and the CD47 expression in tumor cells. The black dashed line represents patients with low CD47 expression (compared to the median CD47 expression in the patient population). The light gray line represents patients with high CD47 expression (compared to the median CD47 expression in the patient population). The solid line corresponds to the average of all patients with high CD47 expression or all patients with low CD47 expression. Time is in months. The survival probability is evaluated by comparing the number of surviving patients over time with the total number of patients at the start of the study. A) The average of all treated patients, where the patients received either monotherapy with an anti-SIRPα antibody or combination therapy of 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 PD-1 inhibitor (ezabenlimab, an anti-PD-1 antagonist antibody). B) The average of patients treated with anti-SIRPα antibody monotherapy.

[0076] Figure 2 There is no correlation shown between the overall survival of patients and the SIRPα expression in tumor cells. The black dashed line represents patients with low SIRPα expression (compared to the median SIRPα expression in the patient population). The light gray line represents patients with high SIRPα expression (compared to the median SIRPα expression in the patient population). The solid line corresponds to the average of all patients with high SIRPα expression or all patients with low SIRPα expression. Time is in months. The survival probability is evaluated by comparing the number of surviving patients over time with the total number of patients at the start of the study. A) The average of all treated patients, where the patients received either monotherapy with an anti-SIRPα antibody or combination therapy of an anti-SIRPα antibody and a PD-1 inhibitor, as Figure 1 shown in the BRIEF DESCRIPTION OF THE DRAWINGS. B) The average of patients treated with anti-SIRPα antibody monotherapy (as Figure 1 shown in the BRIEF DESCRIPTION OF THE DRAWINGS).

[0077] Figure 3 shows the correlation between the overall survival of patients and the expression of SIRPα in CD11b-positive myeloid cells obtained from the tumor microenvironment. A and B, the black dashed line represents patients with low SIRPα expression (CD11b+SIRPa+ myeloid cells less than 65.3%). The light gray line represents patients with high SIRPα expression (CD11b+SIRPa+ myeloid cells at least 65.3%). A) The mean of all treated patients (receiving either anti-SIRPα antibody monotherapy or combination therapy of anti-SIRPα antibody and a PD-1 inhibitor, as described in the Figure 1 accompanying drawings). B) The mean of patients receiving anti-SIRPα antibody monotherapy (as described in the Figure 1 accompanying drawings). C and D, the black dashed line represents patients with low SIRPα expression (CD11b+SIRPa+ myeloid cells less than 60%). The light gray line represents patients with high SIRPα expression (CD11b+SIRPa+ myeloid cells at least 60%). C) The mean of all treated patients (receiving either anti-SIRPα antibody monotherapy or combination therapy of anti-SIRPα antibody and a PD-1 inhibitor, as described in the Figure 1 accompanying drawings). D) The mean of patients receiving anti-SIRPα antibody monotherapy (as described in the Figure 1 accompanying drawings). E and F, the black dashed line represents patients with low SIRPα expression (CD11b+SIRPa+ myeloid cells less than 55%). The light gray line represents patients with high SIRPα expression (CD11b+SIRPa+ myeloid cells at least 55%). The solid line corresponds to the mean of all patients with high SIRPα expression or all patients with low SIRPα expression. The dashed line corresponds to the standard deviation of each group of patients. The survival probability was evaluated by comparing the number of surviving patients over time with the total number of patients at the start of the study. E) The mean of all treated patients (receiving either anti-SIRPα antibody monotherapy or combination therapy of anti-SIRPα antibody and a PD-1 inhibitor, as described in the Figure 1 accompanying drawings). F) The mean of patients receiving anti-SIRPα antibody monotherapy (as described in the Figure 1 accompanying drawings).

[0078] Figure 4 shows the correlation between the gene expression profile (abscissa and left part) of patients who responded positively to the combination therapy of anti-SIRPα antibody and a PD-1 inhibitor and the known gene expression profile in MDSC (ordinate and right part). Detailed Description

[0079] · Definition

[0080] As used herein, the term "antibody" refers to any type of antibody, such as monoclonal antibodies, polyclonal antibodies, recombinant antibodies, chimeric antibodies, and humanized antibodies. The term "antibody" may also refer to a deimmunized antibody, i.e., an antibody in which the T cell epitopes have been removed from the antibody structure and the binding affinity of the antibody to its target SIRPα has not been significantly reduced. Generally, "deimmunized" antibodies are constructed from human constant regions. The antibodies of the present invention include monoclonal antibodies and polyclonal antibodies. As used herein, "monoclonal antibody" refers to a preparation of antibody molecules that have a common heavy and light chain amino acid sequence. In contrast, a "polyclonal" antibody preparation contains a mixture of antibodies with different amino acid sequences. Monoclonal antibodies can be produced by a variety of known techniques (such as phage, bacterial, yeast, or ribosome display) as well as by classical methods exemplified by antibodies derived from hybridomas. 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 produced, expressed, generated, or isolated by recombinant means, such as 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 transgenic for human immunoglobulin genes (such as a mouse), or an antibody produced, expressed, generated, or isolated in any other manner in which a specific immunoglobulin gene sequence (such as a human immunoglobulin gene sequence) is assembled with other DNA sequences. Recombinant antibodies include, for example, chimeric antibodies and humanized antibodies. The antibodies of the present invention include chimeric antibodies. As used herein, "chimeric antibody" refers to an antibody in which the variable domain sequences derived from the germline of a mammalian species (such as a mouse) are grafted onto the constant domain sequences derived from the germline of another mammalian species (such as a human). The antibodies of the present invention include humanized antibodies. As used herein, "humanized antibody" refers to an antibody in which the CDR sequences derived from the germline of another mammalian species (such as a mouse) are grafted onto a human framework sequence.

[0081] As used herein, an "antigen-binding fragment of an antibody" refers to a part of an antibody, i.e., a molecule corresponding to a part of the structure of the antibody of the present invention, which may exhibit antigen-binding ability to SIRPα in its native form; such fragments particularly exhibit antigen-binding specificity for the antigen that is the same as or substantially the same as that of the corresponding full-length antibody. Advantageously, the antigen-binding fragment has a binding affinity similar to that of the corresponding full-length antibody. However, the present invention also includes antigen-binding fragments with reduced antigen-binding affinity compared to the corresponding full-length antibody. 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 the antibody. Antigen-binding fragments of an antibody are fragments containing the hypervariable domains (referred to as CDRs (complementary determining regions)) of the antibody or portions thereof, which contain the antigen recognition site, i.e., the extracellular domain of SIRPα, thus defining the antigen recognition specificity. Antigen-binding fragments of an antibody containing the variable domain that contains the CDRs of the antibody include Fv, dsFv, scFv, Fab, Fab', and F(ab')2. The Fv fragment consists of the VL and VH domains of the antibody linked together by hydrophobic interactions; in the dsFv fragment, the VH:VL heterodimer is stabilized by a disulfide bond; in the scFv fragment, the VL and VH domains are linked to each other by a flexible peptide linker, thus forming a single-chain protein. The Fab fragment is a monomeric fragment obtainable by papain digestion of an antibody, and it contains the entire L chain and the VH-CH1 fragment of the H chain linked together by a disulfide bond. The F(ab')2 fragment can be produced by pepsin digestion of an antibody below the hinge disulfide bond, and it contains two Fab' fragments and a part of the hinge region of the immunoglobulin molecule. The Fab' fragment can be obtained from the F(ab')2 fragment by cleaving the disulfide bond in the hinge region of the F(ab')2 fragment. The F(ab')2 fragment is bivalent, i.e., it contains two antigen-binding sites, similar to the native immunoglobulin molecule; on the other hand, the Fv (the VHVL dimer that constitutes the variable part of Fab), dsFv, scFv, Fab, and Fab' fragments are monovalent, i.e., they contain one antigen-binding site. These basic antigen-binding fragments of the present invention can be combined together to obtain multivalent antigen-binding fragments, such as diabodies, triabodies, or tetravalent antibodies. These multivalent antigen-binding fragments are also part of the present invention.

[0082] The composition particularly refers to a pharmaceutical composition. Such a composition may contain pharmaceutically acceptable components, such as, but not limited to, pharmaceutically suitable excipients, carriers, or vehicles for systemic or topical administration. A pharmaceutically suitable carrier or vehicle refers to non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, and formulations (such as phosphate buffer solutions, distilled water, emulsions (such as oil / water emulsions), wetting agents, etc.), glucose, physiological saline, ethanol, and combinations thereof.

[0083] The term "SIRPα" as used herein refers to signal regulatory peptide alpha from a mammalian species, preferably human SIRPα. SIRPα is also known as CD172a, i.e., tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS-1). SIRPα is an immunoglobulin-like cell surface receptor for CD47. As a docking protein, SIRPα induces the translocation of PTPN6, PTPN11, and other binding partners from the cytosol to the plasma membrane. SIRPα mediates the negative regulation of phagocytosis, mast cell activation, and dendritic cell activation. The binding of CD47 to SIRPα prevents the maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. SIRPα may correspond to the protein cited by Uniprot accession number P78324. Alternatively, SIRPα may correspond to the protein having the amino acid sequence of SEQ ID No.1. The extracellular domain of SIRPα may correspond to the amino acid sequence of SEQ ID No.2, and this extracellular domain may be recognized and bound by the anti-SIRPα antibody or its antigen-binding fragment used in the present invention.

[0084] The term "CD11b" as used herein 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 a protein subunit that forms the heterodimeric integrin α-Mβ-2 (αMβ2) molecule. CD11b is used to identify myeloid cells, particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, more particularly MDSCs. Human CD11b may have an amino acid sequence associated with UniProt accession number P11215, or correspond to the amino acid sequence of SEQ ID No.14.

[0085] The terms "cancer" and "tumor" have their ordinary meanings in the art and refer to a group of diseases involving abnormal cell growth and that may invade or spread to other parts of the body. The term "cancer" also includes primary cancer and metastatic cancer. Cancer is a disease involving abnormal cell growth and that may invade or spread to other parts of the body. According to the present invention, the cancer affecting or that is affecting a patient may be selected from 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 lymphoma, liver cancer, lung cancer (including non-small cell lung cancer), melanoma, mesothelioma, multiple myeloma, myelodysplastic syndromes, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer, adrenal cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal cancer, renal cancer, parotid cancer or uterine cancer, most particularly ovarian cancer, breast cancer (particularly triple negative breast cancer), liver cancer, hepatocellular carcinoma, endometrial cancer or uterine cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer. In a particular embodiment, the cancer affecting the patient is breast cancer, ovarian cancer, liver cancer, endometrial cancer or hepatocellular carcinoma. The tumor microenvironment is the ecosystem around a tumor in the body and it includes immune cells, extracellular matrix, blood vessels and other cells such as fibroblasts. The tumor microenvironment includes the space around the tumor and includes the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and extracellular matrix. The tumor is closely related to and often interacts with the surrounding microenvironment. The immune cells in the microenvironment can affect the growth and evolution of cancer cells.

[0086] As used herein, "treatment" or "therapy" refers to a method of obtaining a beneficial or desired result, including a clinical result. For the purposes of the present invention, a beneficial or desired clinical result includes, but is not limited to, more than one of the following: alleviation of one or more symptoms caused by the disease, reduction of the severity of the disease, stabilization of the disease condition (e.g., preventing or delaying disease progression), prevention or delay of the spread of the disease, prevention or delay of the recurrence of the disease, delay or slowing of the progression of the disease, improvement of the disease state, providing disease remission (partial or complete), reduction of the dosage of one or more other drugs required or used to treat the disease, improvement of the quality of life, achieving progression-free survival (PFS), increasing the time to disease progression and / or extending survival (particularly overall survival (OS)), prevention or alleviation of side effects of current or upcoming therapies.

[0087] The terms "effective dose", "effective amount", or "therapeutically effective dose" are defined as a dose sufficient to achieve or at least partially achieve the desired effect. The term "effective dose" is intended to include an amount sufficient to cure or at least partially inhibit a disease and its complications, or to alleviate the symptoms of the disease in a patient already suffering from the disease. The effective amount or effective dose for this use depends on the condition to be treated, the antibody construct administered, the treatment context and 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 body size (weight, body surface area, or organ size) and / or condition (age and overall health), and the overall status of the patient's own immune system. The appropriate dose can be adjusted to be administered to the patient either as a single dose or in multiple doses to obtain the optimal therapeutic effect. In one particular embodiment, the effective dose is a dose capable of reducing (or shrinking) the tumor volume or preventing the tumor volume from increasing in a patient undergoing treatment. For example, a "therapeutically acceptable amount" of a therapeutic agent (such as an antibody or an antigen-binding fragment thereof) can be from about 0.1 mg to about 50 mg per kilogram of patient body weight (drug / patient weight).

[0088] A "marker" (or biomarker) is defined as a measurable biochemical, molecular, or cellular alteration in a biological tissue (such as tissue, cells, or body fluid) that indicates, for example, a functional association with the normal or abnormal processes of a condition or disease. The term "biomarker" refers to a molecule that can be precisely and reproducibly measured, enabling the provision of an objectively measurable and assessable "signature" as an indicator of normal biological processes, pathogenic processes, or pharmacological responses. In the context of the present invention, the biomarker corresponds to a biomolecule expressed by and / or present within human cells. Thus, the biomarkers in the present invention include protein biomarkers, gene biomarkers (corresponding to the transcriptional products of genes), and epigenetic biomarkers (such as corresponding to DNA methylation). In the present invention, the biomarkers include DNA, RNA, and proteins. CD11b and SIRPα are considered markers in the context of the present invention.

[0089] A patient can be any person who has ever had, is suspected of having, or has cancer. In particular, a subject can be any person who has cancer and has been correspondingly diagnosed. A patient can be a child, an adolescent, or an adult. A subject can have received or not received treatment for cancer-related symptoms. In one embodiment of the present invention, the subject is undergoing cancer treatment or has previously received cancer treatment, such as chemotherapy, radiotherapy, immunotherapy, hormone therapy, or any suitable method. In another embodiment of the present invention, the subject has not received or has not yet received cancer treatment. The present invention can optionally include determining one or more clinical factors of the subject, such as selected from gender, age, body mass index, and health history.

[0090] A biological sample obtained from a patient can be any biological sample, such as tissue, blood, urine, whole cell lysate, biopsy tissue, tumor, 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 tissue, tumor, and cell samples can also be obtained without invasive surgery, such as by puncturing a subject with a fine needle and aspirating cell material or by biopsy. In certain embodiments, a sample collected from a patient can be processed or processed to obtain a processed biological sample, such as a supernatant, whole cell lysate, or cell fraction or extract obtained directly from the patient. In other embodiments, a biological sample obtained from a patient can also be used without further processing or processing. In a preferred embodiment, the biological sample obtained from a subject is tissue (especially tissue from a tumor or tumor extract), preferably obtained by biopsy. A biological sample obtained from a subject can be, for example, a sample removed or collected from or easily removed from an internal organ, tissue, or tumor (especially a tumor) of the subject, or a biological fluid from the subject, such as blood, serum, plasma, tumor microenvironment, or urine. A biological sample collected or removed from a subject can be, for example, a sample containing cancer cells that has been removed or collected from or easily removed from the tissue (especially a tumor) of the subject. A step of lysing cells (especially lysing cancer cells contained in the biological sample) can be performed in advance so that nucleic acids or proteins and / or polypeptides and / or peptides (if applicable) can be directly used for analysis.

[0091] As used herein, "myeloid cells" refers to blood cells or tumor microenvironment cells derived from progenitor cells (applicable to granulocytes, monocytes, dendritic cells, erythrocytes, or platelets). Myeloid cells include macrophages, MDSCs, myeloid dendritic cells, eosinophils, neutrophils, basophils, erythrocytes, and platelets. In a particular embodiment, myeloid cells refer to tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils.

[0092] · Anti-SIRPα compound

[0093] The compositions used in the present invention, or the compositions used in the methods of the present invention, comprise anti-SIRPα compounds that inhibit the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, especially anti-SIRPα antibodies or antigen-binding fragments thereof. The term "anti-SIRPα compound" includes anti-SIRPα antibodies and antigen-binding fragments thereof that inhibit the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0094] In a particular embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof is an antagonist of the binding between SIRPα and CD47; that is, it reduces the interaction between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0095] In a particular embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof is an antagonist of the signaling pathway induced by the interaction between SIRPα and CD47; that is, when SIRPα and CD47 interact, it reduces or inhibits the intracellular molecular pathway that is normally activated in the absence of the anti-SIRPα antibody or antigen-binding fragment thereof.

[0096] In a preferred embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof does not inhibit the interaction between human SIRPg and human CD47.

[0097] In a particular embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof specifically binds to human SIRPαv1 and human SIRPαv2, thereby being capable of treating patients expressing any combination of SIRPα alleles selected from SIRPαv1 and SIRPαv2.

[0098] In a particular embodiment, 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.

[0099] When an antibody or its antigen-binding fragment antagonizes the CD47 / SIRPα interaction, it can be considered that the antibody or its antigen-binding fragment inhibits the interaction between SIRPα and CD47. When used in the negative form, for example, when an antibody or its antigen-binding fragment does not inhibit the interaction between human SIRPg and human CD47 respectively, it means that the antibody or its antigen-binding fragment does not antagonize the CD47 / SIRPg interaction respectively. Reducing or inhibiting the binding of (human) CD47 to (human) SIRPα means that an antibody, its antigen-binding fragment, antigen-binding antibody mimetic or modified antibody reduces the interaction between SIRPα and CD47, that is, the antibody or its antigen-binding fragment partially or completely inhibits the binding of human CD47 to human SIRPα, or in other words, the antibody or its antigen-binding fragment specifically binds to human SIRPα and antagonizes the interaction between human SIRPα and human CD47. In particular, in a binding assay, compared with a negative control molecule, an anti-human SIRPα antibody or its antigen-binding fragment can reduce or inhibit the binding of (human) CD47 to (human) SIRPα by at least 50%, preferably 60%, more preferably 70%, more preferably 80%, most preferably 90%, and in certain embodiments 100%. In particular, in a binding assay, compared with a negative control molecule, an anti-SIRPα antibody or its antigen-binding fragment can reduce or inhibit the binding of human CD47 to human SIRPα by 50% to 100%, more preferably 50% to 90%.

[0100] In a particular embodiment of the invention, the anti-SIRPα antibody or its antigen-binding fragment is an anti-SIRPα antagonist antibody or its antigen-binding fragment that antagonizes (i.e., reduces or inhibits) the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0101] In a particular embodiment of the invention, the anti-SIRPα antibody or its antigen-binding fragment comprises:

[0102] i) a heavy chain variable domain that comprises an amino acid sequence as set forth in SEQ ID No: 3, SEQ ID No: 4, SEQ ID No: 5, SEQ ID No: 6, SEQ ID No: 7 or SEQ ID No: 8;

[0103] ii) a light chain variable domain that comprises an amino acid sequence as set forth in SEQ ID No: 9 or SEQ ID No: 10.

[0104] In a particular embodiment of the invention, the anti-SIRPα antibody or its antigen-binding fragment comprises:

[0105] (i) A heavy chain variable domain, which heavy chain variable domain comprises:

[0106] - A heavy chain CDR1 (HCDR1) domain, comprising the amino acid sequence shown in SEQ ID No. 15 or consisting thereof; and

[0107] - A heavy chain CDR2 (HCDR2) domain, comprising the amino acid sequence shown in SEQ ID No. 16 or SEQ ID No. 17 or consisting thereof; and

[0108] - A heavy chain CDR3 (HCDR3) domain, comprising the amino acid sequence shown in SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20 or SEQ ID No. 21 or consisting thereof; and

[0109] (ii) A light chain variable domain, which light chain variable domain comprises:

[0110] - A light chain CDR1 (LCDR1) domain, comprising the amino acid sequence shown in SEQ ID No. 22 or consisting thereof; and

[0111] - A light chain CDR2 (LCDR2) domain, comprising the amino acid sequence shown in SEQ ID No. 23 or consisting thereof, and;

[0112] - A light chain CDR3 (LCDR3) domain, comprising the amino acid sequence shown in SEQ ID No. 24 or consisting thereof.

[0113] In a particular embodiment, the anti-SIRPα antibody or antigen-binding fragment thereof comprises:

[0114] · A heavy chain variable domain, which heavy chain variable domain comprises:

[0115] - A heavy chain CDR1 (HCDR1) domain, comprising the amino acid sequence shown in SEQ ID No. 15 or consisting thereof; and

[0116] - A heavy chain CDR2 (HCDR2) domain, comprising the amino acid sequence shown in SEQ ID No. 17 or consisting thereof; and

[0117] - A heavy chain CDR3 (HCDR3) domain, comprising the amino acid sequence shown in SEQ ID No. 21 or consisting thereof; and

[0118] · A light chain variable domain, which light chain variable domain comprises:

[0119] - The light chain CDR1 (LCDR1) domain, comprising the amino acid sequence shown in SEQ ID No. 22 or consisting thereof;

[0120] - The light chain CDR2 (LCDR2) domain, comprising the amino acid sequence shown in SEQ ID No. 23 or consisting thereof;

[0121] - The light chain CDR3 (LCDR3) domain, comprising the amino acid sequence shown in SEQ ID No. 24 or consisting thereof.

[0122] In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment is a monoclonal antibody. In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment is a humanized antibody. In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment is a humanized monoclonal antibody. In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment is selected from Fab, Fab’, Fab’-SH, Fv, single-chain variable fragment (scFv), double-chain variable fragment (dsFv), and (Fab’)2 fragments. In particular, the antibody or its antigen-binding fragment comprises a constant chain belonging to the IgG1, IgG2, IgG3, or IgG4 subclass (especially the IgG1 or IgG4 subclass, most especially the IgG4 subclass).

[0123] In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment 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.

[0124] In a particular embodiment of the present invention, the anti-SIRPα antibody comprises: a heavy chain 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.

[0125] In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment comprises: 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.

[0126] In a particular embodiment of the present invention, the anti-SIRPα antibody comprises: 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.

[0127] In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment comprises: 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.

[0128] In a particular embodiment of the present invention, the anti-SIRPα antibody comprises: 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.

[0129] In a particular embodiment of the present invention, the anti-SIRPα antibody or its antigen-binding fragment useful for the invention disclosed herein includes SEQ ID NO: 8 and SEQ ID NO: 9 of WO2020 / 099653 or its SIRPa-binding portion, such as an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the foregoing CDRs, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0130] Other exemplary anti-SIRPa antibodies useful for the invention disclosed herein include: SEQ ID NO: 7 and SEQ ID NO: 8 of WO2019 / 023347, SEQ ID NO: 15 and SEQ ID NO: 16 of WO2019 / 023347, or the SIRPa-binding portion of any of the foregoing, such as an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0131] In a particular embodiment of the present invention, the anti-SIRPα antibody or antigen-binding fragment thereof useful in the invention disclosed herein can be any of the antibodies disclosed in the PCT publication numbered WO2022 / 254379, particularly the antibodies numbered A, A4, A10, A11, E, E22. More particularly, the anti-SIRPα antibody or antigen-binding fragment thereof comprises the CDRs disclosed in any one of Tables 1 to 10 of WO2022 / 254379. Most particularly, the anti-SIRPα antibody or antigen-binding fragment thereof comprises the heavy chain variable region of SEQ ID No. 100, SEQ ID No. 111, SEQ ID No. 113, SEQ ID No. 104 or SEQ ID No. 221 of WO2022 / 254379 and the light chain variable region of SEQ ID No. 105, SEQ ID No. 125, SEQ ID No. 126, SEQ ID No. 109 or SEQ ID No. 222 of WO2022 / 254379, or has a heavy chain of SEQ ID No. 131, SEQ ID No. 135, SEQ ID No. 141, SEQ ID No. 147, SEQ ID No. 217 or SEQ ID No. 219 and a light chain of SEQ ID No. 174, SEQ ID No. 178, SEQ ID No. 184, SEQ ID No. 190, SEQ ID No. 218 or SEQ ID No. 220. In particular, the SIRPα antibody or antigen-binding fragment thereof useful in the invention disclosed herein can have any one of the following combinations of heavy chain variable region and light chain variable region: 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, the anti-SIRPα antibody or antigen-binding fragment thereof useful in the invention disclosed herein can have any one of the following combinations of heavy chain and light chain: 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.

[0132] Other exemplary anti-SIRPa antibodies useful in the invention of the present disclosure 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 the SIRPa-binding portion of any of the foregoing, such as an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0133] Other exemplary anti-SIRPa antibodies useful in the invention of the present disclosure include: 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:121 and SEQ ID NO:140 of WO2021 / 226576, SEQ ID NO:122 and SEQ ID NO:141 of WO2021 / 226576; wherein the antibody may optionally be linked to a constant region (e.g., a human IgG1, IgG2, IgG3 or IgG4 constant region or a variant thereof); the SIRPa-binding portion of any of the foregoing (e.g., an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc.); which may optionally be linked to a pharmacokinetic enhancer.

[0134] Other exemplary anti-SIRPa antibodies that can be used in the inventions of the present disclosure include: 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, 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; wherein the antibody is optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region or a variant thereof); the SIRPa-binding portion of any of the foregoing (e.g., an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc.); they can optionally be linked to a pharmacokinetic enhancer.

[0135] Other exemplary anti-SIRPa antibodies that can be used in the inventions of the present disclosure include: the VH region shown in SEQ ID NO: 169 and the VL region shown in SEQ ID NO: 170 of WO2021174127; the VH region shown in SEQ ID NO: 171 and the VL region shown in SEQ ID NO: 172 of WO2021174127; the VH region shown in SEQ ID NO: 173 and the VL region shown in SEQ ID NO: 174 of WO2021174127; the VH region shown in SEQ ID NO: 175 and the VL region shown in SEQ ID NO: 176 of WO2021174127; the VH region shown in SEQ ID NO: 177 and the VL region shown in SEQ ID NO: 178 of WO2021174127; the VH region shown in SEQ ID NO: 179 and the VL region shown in SEQ ID NO: 180 of WO2021174127; the VH region shown in SEQ ID NO: 181 and the VL region shown in SEQ ID NO: 182 of WO2021174127; the VH region shown in SEQ ID NO: 183 and the VL region shown in SEQ ID NO: 184 or 227 of WO2021174127; the VH region shown in SEQ ID NO: 185 and the VL region shown in SEQ ID NO: 186 of WO2021174127; the VH region shown in SEQ ID NO: 187 and the VL region shown in SEQ ID NO: 188 of WO2021174127; the VH region shown in SEQ ID NO: 189 and the VL region shown in SEQ ID NO: 190 of WO2021174127; the VH region shown in SEQ ID NO: 191 and the VL region shown in SEQ ID NO: 192 of WO2021174127; the VH region shown in SEQ ID NO: 193 and the VL region shown in SEQ ID NO: 194 of WO2021174127; the VH region shown in SEQ ID NO: 195 and the VL region shown in SEQ ID NO: 196 of WO2021174127; the VH region shown in SEQ ID NO: 197 and the VL region shown in SEQ ID NO: 198 of WO2021174127; the VH region shown in SEQ ID NO: 199 and the VL region shown in SEQ ID NO: 200 of WO2021174127; the VH region shown in SEQ ID NO: 201 and the VL region shown in SEQ ID NO: 202 of WO2021174127; the VH region shown in SEQ ID NO: 203 and the SEQThe VL region shown in IDNO: 204, the VH region shown in SEQ ID NO: 205 of WO2021174127, and the VL region shown 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, the VH region shown in SEQ ID NO: 219 of WO2021174127, and the VL region shown in SEQ ID NO: 220, the VH region shown in SEQ ID NO: 221 of WO2021174127 and the VL region shown in SEQ ID NO: 222 or the VH region shown in SEQ ID NO: 223 of WO2021174127 and the VL region shown in SEQ ID NO: 224; wherein the antibody is optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3 or IgG4 constant region or a variant thereof); the SIRPa binding portion of any of the foregoing (e.g., an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc.); they may optionally be linked to a pharmacokinetic enhancer.

[0136] Other exemplary anti-SIRPa antibodies useful in the invention of the present disclosure include: SEQ ID NO: 35 and SEQ ID NO: 41 of WO2019 / 226973, or their SIRPa binding portions, such as antigen-binding fragments of anti-SIRPa antibodies, anti-SIRPa antibodies or antigen fragments comprising the foregoing CDRs, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0137] Other exemplary anti-SIRPa antibodies useful for the invention of the present disclosure 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 the SIRPa-binding portion of any of the foregoing, such as an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0138] Other exemplary anti-SIRPa antibodies useful for the invention of the present disclosure include: SEQ ID NO: 64 and SEQ ID NO: 78 of US20210347908, SEQ ID NO: 65 and SEQ ID NO: 79 of US20210347908, SEQ ID NO: 65 and SEQ ID NO: 80 of US20210347908, SEQ ID NO: 66 and SEQ ID NO: 81 of US20210347908, SEQ ID NO: 65 and SEQ ID NO: 82 of US20210347908, SEQ ID NO: 67 and SEQ ID NO: 83 of US20210347908, SEQ ID NO: 68 and SEQ ID NO: 82 of US20210347908, or SEQ ID NO: 65 and SEQ ID NO: 84 of US20210347908; wherein the antibody may optionally be linked to a constant region (e.g., a human IgG1, IgG2, IgG3 or IgG4 constant region or a variant thereof); the SIRPa-binding portion of any of the foregoing (such as an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc.); which may optionally be linked to a pharmacokinetic enhancer.

[0139] Other exemplary anti-SIRPa antibodies useful for the inventions of the present disclosure 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 of WO2020 / 102422, SEQ ID NO:89 and SEQ ID NO:72 of WO2020 / 102422, SEQ ID NO:90 and SEQ ID NO:73 of WO2020 / 102422, SEQ ID NO:91 and SEQ ID NO:74 of WO2020 / 102422, SEQ ID NO:91 and SEQ ID NO:75 of WO2020 / 102422, SEQ ID NO:91 and SEQ ID NO:76 of WO2020 / 102422, SEQ ID NO:92 and SEQ ID NO:74 of WO2020 / 102422, SEQ ID NO:92 and SEQ ID NO:75 of WO2020 / 102422, SEQ ID NO:92 and SEQ ID NO:76 of WO2020 / 102422, 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 / 102422, SEQ ID of WO2020 / 102422ID NO: 95 and SEQ ID NO: 79, 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; wherein the antibody is optionally linked to a constant region (e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region or a variant thereof); an SIRPa binding portion of any of the foregoing (e.g., an antigen-binding fragment of an anti-SIRPa antibody, an anti-SIRPa antibody or antigen fragment comprising the CDR of any of the foregoing, etc.); they may optionally be linked to a pharmacokinetic enhancer.

[0140] Other exemplary anti-SIRPa antibodies useful in the invention of the present disclosure include: BR105 (Zhejiang Biolun Therapeutics Co., Ltd.; see clinical trial number NCT05351697); ELA026 (Electra Therapeutics; see clinical trial number NCT05416307); IBI397 (Innovent Biologics, Inc.; Alector; see clinical trial number NCT05245916); BSI-050 (Bio-XCell); BSI-082 (Bio-XCell); ES004 (Cura Oncology); APX701 (Apexigen); and BYON4228 (Byondis).

[0141] The anti-SIRPa antibodies of the present invention may include: the anti-SIRPa antibodies of any one of WO0066159, WO0140307, WO200140307, WO2009131453, WO2013056352, WO2014149477, WO2014186761, WO2015138600, WO2016063233, WO2016205042, WO2017178653, WO2018008470, WO2018026600, WO2018057669, WO2018107058, WO2018141964, WO2018160739, WO2018190719, WO2018210793, WO2019023347, WO2019183266, WO2019200462, WO2019226973, WO2020006374, WO2020013170, WO2020033646, WO2020068752, WO2020102422, WO2020099653, WO2020180811, WO2020247820, WO2021022044, WO2021032078, WO2021076908, WO2021129697, WO2021174127, WO2021185273, CN111635458, WO2021222746, WO2021226576, WO2021226591, CN113735973, CN111995682, CN112010979 or CN112574310 (each document is incorporated herein by reference in its entirety), or the SIRPa binding portion of any of the foregoing, such as the anti-SIRPa antibody or CD47 fragment contained in any of the foregoing, its SIRPa binding fragment (such as the antigen-binding fragment of the anti-SIRPa antibody), the anti-SIRPa antibody or antigen fragment containing its CDR, etc., which may optionally be linked to a pharmacokinetic enhancer.

[0142] All of the cited documents that disclose anti-SIRPα antibodies or their antigen-binding fragments are incorporated herein by reference. Any one of these antibodies can be used in the same manner as the antibodies used in the working examples disclosed in the present disclosure according to any method or use disclosed in the present invention.

[0143] · A patient may respond positively to treatment with an anti-SIRPα compound as defined herein.

[0144] One aspect of the present invention provides a composition comprising an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, for use in treating cancer in a patient having:

[0145] - at least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs, and / or tumor-associated neutrophils) present in the tumor microenvironment express the biomarkers CD11b and SIRPα.

[0146] In a preferred embodiment, at least 55%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64% or at least 65%, particularly at least 65.3%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90% of the myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs, and / or tumor-associated neutrophils) present in the tumor microenvironment of the patient express the biomarkers CD11b and SIRPα. In a particular embodiment, at least 55%, particularly at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, particularly at least 65.3%, at least 70%, at least 75%, at least 80%, at least 90% or at least 95% of the tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly MDSCs) present in the tumor microenvironment of the patient express the biomarkers CD11b and SIRPα. When several types of myeloid cells are selected to measure the percentage of myeloid cells expressing CD11b and SIRPα, the percentage of cells expressing CD11b and SIRPα is measured in each selected type of myeloid cell, and the measurement results are aggregated to obtain the measurement results of CD11b and SIRPα expression in myeloid cells.

[0147] Myeloid cells expressing these markers (including tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs) can be detected in a biological sample previously obtained from a patient according to methods known in the art, such as immunoassays for SIRPα and CD11b, gene expression profiling, fluorescence detection, enzyme activity assays, chemiluminescence detection, immunohistochemistry, polymerase chain reaction, reverse transcription polymerase chain reaction, antibody binding, receptor binding arrays, target-specific primer extension, ELISA, radiolabeling. For example, the expression of CD11b and SIRPα on the surface of myeloid cells present in a biological sample can be measured by immunohistochemistry or flow cytometry using several different antibodies or fluorescent dyes known to interact with one of the listed markers.

[0148] In a preferred embodiment, at least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells (particularly tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils) present in the tumor microenvironment of a patient express the biomarkers CD11b and SIRPα.

[0149] In one embodiment of the invention, an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47 is administered to a patient at least once, wherein at least 55%, particularly at least 60%, particularly at least 65.3% of the myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, more particularly MDSCs) present in the tumor microenvironment of the patient express SIRPα and CD11b.

[0150] In a particular embodiment of the invention, a composition is provided that comprises an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, particularly between human SIRPα and human CD47, for use in the treatment of a cancer patient having:

[0151] - at least 55%, particularly at least 60%, particularly at least 65.3%, most preferably at least 70% of the myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, and / or tumor-associated neutrophils) present in the tumor microenvironment express the biomarkers CD11b and SIRPα.

[0152] In a preferred embodiment, myeloid cells are present in the tumor microenvironment of a patient. These cells can be detected in a biological sample obtained from the patient, particularly a biopsy sample. Cell detection can be carried out by methods known in the art, such as detecting specific molecular markers associated with myeloid cells by IHC or flow cytometry.

[0153] In a preferred embodiment, the use of the composition for treating a patient suffering from SIRPα-positive cancer, PD-1-positive cancer or PD-L1-positive cancer, particularly a cancer with solid tumors expressing or overexpressing SIRPα, PD-1 and / or PD-L1, wherein the patient is identified as exhibiting the biomarker disclosed in the present invention.

[0154] In a preferred embodiment, the use of the composition for treating a patient suffering from solid cancer, particularly a cancer with advanced solid tumors, more particularly adrenocortical carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (more particularly non-small cell lung cancer (NSCLC)), cervical cancer or colorectal cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, wherein the patient is identified as exhibiting the biomarker disclosed in the present invention.

[0155] · A second therapeutic compound that can be administered to a patient

[0156] In some embodiments, an anti-SIRPα compound for use in the treatment method or use of the present invention is administered to a patient in combination with a standard or conventional or standard-of-care treatment. Accordingly, the present invention relates to a combination of an anti-SIRPα compound for use in the treatment method or use of the present invention and a conventional treatment for treating cancer. The term "standard or conventional treatment or standard-of-care treatment" as used herein refers to any cancer treatment (drug, surgery, radiotherapy, etc.) that is typically administered to cancer patients.

[0157] In some embodiments, an anti-SIRPα compound for use in the treatment method or use of the present invention is administered to a patient in combination with at least one other therapeutic agent suitable for treating cancer in a combination therapy. The administration can be carried out simultaneously, separately or sequentially. For simultaneous administration, depending on the circumstances, the drugs can be administered as one composition or as separate compositions. The other therapeutic agents are generally related to the disease 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 regulators, hormone regulators and other drugs as described below.

[0158] An anti-SIRPα antibody or an antigen-binding fragment thereof can be administered in combination therapy with at least one other therapeutic compound. The anti-SIRPα antibody or an antigen-binding fragment thereof can also be administered in combination therapy with several (i.e., more than one, such as two, three, or four) other therapeutic compounds.

[0159] In some embodiments, the anti-SIRPα compound for the treatment method or use of the present invention is used in combination therapy with a second therapeutic agent.

[0160] The second therapeutic agent can be selected from: chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents, hormonal therapeutic agents, cell therapeutic agents, antibiotics, and probiotics, particularly immunotherapeutic agents, and the immunotherapeutic agents are selected from immune checkpoint inhibitors or activators of adaptive immune cells, particularly selected from 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. In particular, the therapeutic agent is an antibody. Use of a combination of drugs for the treatment of cancer.

[0161] In one embodiment, the anti-PD-1 antibody can be selected from 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 (see 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), MGA012 (see WO2017 / 19846), or IBI308 (see WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540), the monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4 described in WO2006 / 121168.

[0162] In a particular embodiment of the invention, the second therapeutic agent is an anti-PD-1 antagonist or an anti-PD-L1 antagonist. In a particular embodiment of the invention, the second therapeutic agent is an anti-PD-1 antibody or an anti-PD-L1 antibody, more particularly an anti-PD-1 antagonist antibody or an anti-PD-L1 antagonist antibody. In a particular embodiment of the invention, the second therapeutic agent is a PD-1 antagonist, particularly selected from the following antibodies: pembrolizumab, nivolumab, pidilizumab, tislelizumab, spartalizumab, ebratuzumab, preferably ebratuzumab. In a particular embodiment of the invention, the second therapeutic agent is an anti-PD-L1 antagonist, particularly selected from avelumab (Bavencio), durvalumab (Imfinzi), atezolizumab (Tecentriq).

[0163] In a particular embodiment of the invention, the second therapeutic agent is administered to the patient in any therapeutically effective amount. In certain embodiments, the therapeutically acceptable amount is from about 0.1 mg to about 50 mg (drug / patient body weight) per kilogram of patient body weight.

[0164] In a particular embodiment, the second therapeutic agent is selected from: immune checkpoint inhibitors or activators, more particularly, the second therapeutic agent is an anti-PD-1 compound or an anti-PD-L1 compound. In a preferred embodiment, the second therapeutic agent is a PD-1 antagonist compound, an anti-PD-1 antagonist antibody. In a preferred embodiment, the second therapeutic agent is an anti-PD-L1 antagonist compound, more particularly an anti-PD-L1 antagonist antibody, particularly avelumab (Bavencio), durvalumab (Imfinzi), atezolizumab (Tecentriq).

[0165] The second therapeutic agent can be administered simultaneously or separately with the anti-SIRPα antibody or an antigen-binding fragment thereof, particularly subsequently or sequentially. The second therapeutic agent can be administered according to the same dosing schedule as the anti-SIRPα antibody or an antigen-binding fragment thereof, either simultaneously or at different times.

[0166] The invention also relates to an anti-SIRPα compound of any of the embodiments disclosed herein, which is used alone or in combination with a second therapeutic agent as defined herein and / or a pharmaceutically suitable carrier for combination therapy for treating cancer, and another therapy includes using a drug comprising a chemotherapeutic agent, a radiotherapy agent, an immunotherapeutic agent (such as a tumor-targeting monoclonal antibody), a hormone therapy agent, a cell therapy agent (such as CAR-T cells), an immunosuppressant, a proapoptotic agent, an antibiotic, a targeted cancer therapy and / or a probiotic, particularly for simultaneous, separate or sequential administration to a patient in need.

[0167] The present invention also relates to the use of an anti-SIRPα compound of any of the embodiments disclosed herein, alone or in combination with a second therapeutic agent and / or a pharmaceutically suitable carrier as defined herein, in combination therapy for treating cancer, the other therapy including surgery, chemotherapy, radiotherapy, stem cell therapy, immunotherapy, targeted therapy, particularly for simultaneous, separate or sequential administration to a patient in need under one of the listed therapies.

[0168] · Route of administration

[0169] The uses and methods described herein allow the anti-SIRPα compound to be administered by any acceptable route. In a typical embodiment, the pharmaceutical composition is formulated according to conventional procedures into a pharmaceutical composition suitable for intravenous administration to humans. Generally, the composition for intravenous administration is a solution of a sterile isotonic buffered solution. If necessary, the drug may also contain solubilizing agents and local anesthetics (such as lidocaine) to relieve the pain at the injection site. Generally, the ingredients may be provided separately or mixed together in unit dosage form, for example as a dry lyophilized powder or an anhydrous concentrate in a sealed container (such as an ampoule labeled with the content of the active ingredient). If the drug is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. If the drug is administered by injection, an ampoule containing sterile water for injection or saline can be provided to mix all the ingredients before administration. In some embodiments, the anti-SIRPα antibody or its antigen-binding fragment is administered orally, subcutaneously, parenterally (such as in liquid form), rectally (such as in the form of a suppository), topically (such as in the form of a transdermal patch, ointment or cream) or intranasally. In other words, the use of the anti-SIRPα compound and its method of use can be by an administration route including oral administration, local administration to the gastrointestinal tract (GI) (particularly oral administration) (particularly for treating cancers related to the digestive tract). In particular, compositions suitable for systemic administration are provided herein, particularly suitable for parenteral or enteral administration, particularly suitable for intravenous injection, infusion or oral administration. Enteral administration can be local administration to the digestive tract or systemic administration. The administration route may include the use of a device (“delivery device”) that allows the administration (particularly injection or infusion) of the composition. Examples of administration routes include but are not limited to: the use of the active compound as a solution (particularly a sterile aqueous solution, suspension), solid (particularly a lyophilized solid), adsorbed on a patch, suspended or reconstituted and administered as a solution, as a pill, tablet or other suitable solid form for oral administration (particularly delayed or sustained release). Preferably, the anti-SIRPα compound is administered subcutaneously or intravenously, preferably intravenously.

[0170] In one embodiment of the present invention, a kit is provided, which comprises an anti-SIRPα compound (i.e., an antibody or its antigen-binding fragment) for use in any of the embodiments disclosed herein, and a device suitable for topical administration, particularly a subcutaneous or oral administration device, particularly a device comprising a pre-filled syringe, or particularly a needle-free device. In particular, the device suitable for topical administration contains a prescription dose of the anti-SIRPα compound for directly administering the anti-SIRPα compound to a patient without the need for dilution, formulation, or reconstitution of the product prior to administration. Optionally, the kit may be accompanied by instructions in a form prescribed by a government agency that regulates the manufacture, use, or sale of drugs or biological products, which reflect the approval of the agency for the manufacture, use, or sale for human administration.

[0171] · Cancer

[0172] The uses described herein and the methods described herein can be used to treat cancer. In particular, the uses described herein and the methods described herein can be used to treat solid cancers and liquid cancers. The term "cancer" has its ordinary meaning in the art and refers to a group of diseases involving abnormal cell growth and that may invade or spread to other parts of the body. The term "cancer" includes primary cancer and metastatic cancer. Cancers that can be treated by the methods and compositions of the present invention include, but are not limited to, bladder cancer, blood cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer (including triple-negative breast cancer), colon cancer, esophageal cancer, gastrointestinal cancer, gingival cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer, or uterine cancer. In a particular aspect of the present invention, the uses and methods described herein are used to treat cancer in a patient, wherein the cancer is one of ovarian cancer, pancreatic cancer, ampullary cancer, microsatellite stable (MSS) cancer, microsatellite unstable (MSI) cancer, colorectal cancer (particularly MSI and MSS colorectal cancer), fibrolamellar cancer, breast cancer, melanoma, kidney cancer, lung cancer (particularly non-small cell lung cancer (NSCLC)), head and neck cancer (particularly head and neck squamous cell carcinoma (HNSCC)), stomach cancer, liver cancer, endometrial cancer, and hepatocellular carcinoma.

[0173] The uses described herein and the methods described herein can be used to treat cancers in which cancer cells express low tumor-specific antigens (such as CD47 and PD-L1 antigens).

[0174] In a particular aspect, the uses described herein and the methods described herein can be used to treat 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 with solid tumors that express or overexpress SIRPα, CD47, PD-1 and / or PD-L1. SIRPα, CD47, PD-L1 or PD-1 positive cancers refer to 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 cells or immune cells that express SIRPα, CD47, PD-L1 or PD-1 on their cell surface. Cancers can be classified as SIRPα, CD47, PD-L1 or PD-1 positive cancer subtypes by immunohistochemistry using monoclonal antibodies against SIRPα, CD47, PD-1 or PD-L1.

[0175] In a particular aspect of the present invention, the uses and methods described herein are used to treat cancer in a patient who has been diagnosed with a cancer having a solid tumor, particularly a cancer having an advanced solid tumor, more particularly adrenal cancer, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (more particularly non-small cell lung cancer (NSCLC)), cervical cancer or colorectal cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer. A cancer having a solid tumor may not contain any fluid or cysts. The solid tumor may correspond to a sarcoma or a carcinoma of epithelial origin.

[0176] In a particular aspect of the invention, the uses and methods described herein are for treating cancer in a patient having a liquid or solid cancer, particularly bladder cancer, blood cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer (including triple-negative breast cancer), colon cancer, esophageal cancer, gastrointestinal cancer, gum cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer or uterine cancer. In a particular aspect of the invention, the uses and methods described herein are for treating cancer in a patient, wherein the cancer is one of ovarian cancer, pancreatic cancer, ampullary cancer, microsatellite stable (MSS) cancer, microsatellite unstable (MSI) cancer, colorectal cancer (particularly MSI and MSS colorectal cancer), fibrolamellar cancer, breast cancer, melanoma, kidney cancer, lung cancer (particularly non-small cell lung cancer (NSCLC)), head and neck cancer (particularly head and neck squamous cell carcinoma (HNSCC)), stomach cancer, liver cancer, endometrial cancer and hepatocellular carcinoma; the cancer is SIRPα, CD47, PD-L1 or PD-1 positive, as detailed above.

[0177] · Patient

[0178] In a particular aspect of the invention, the uses and methods described herein are for treating a patient who has received cancer treatment prior to use and who exhibits resistance to treatment and / or disease progression despite ongoing treatment. The prior treatment can include standard or conventional treatment for any cancer. The term "standard or conventional treatment" refers to any cancer treatment (drugs, surgery, radiotherapy, etc.) typically administered to cancer patients.

[0179] In a particular aspect of the invention, the uses and methods described herein are for treating a patient who has received, is receiving or will receive immune checkpoint inhibitor treatment.

[0180] In a particular aspect of the invention, the uses and methods described herein are for treating a patient who has been treated with an immune checkpoint inhibitor or activator (particularly with 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, more particularly with an anti-PD-1 or anti-PD-L1 antibody) and who does not have a positive response to the administration of the immune checkpoint inhibitor or activator (i.e., the patient experiences disease progression and / or does not experience disease regression).

[0181] Accordingly, the uses and methods described herein can be used for monotherapy or combination therapy for treating patients identified as above.

[0182] In a particular aspect of the invention, the uses and methods described herein are for treating patients who have not received, are not receiving, or will not receive immune checkpoint inhibitor therapy in the future.

[0183] In a particular aspect of the invention, the uses and methods described herein are for treating patients who have not received anti-PD-1 antibody or anti-PD-L1 antibody (especially anti-PD-1 antagonist antibody or anti-PD-L1 antagonist antibody) therapy prior to administration of an anti-SIRPα compound.

[0184] In a particular embodiment, the patient has at least one SIRPαv1 allele (i.e., the patient is homozygous and has two SIRPαv1 alleles, or is heterozygous for SIRPα and has one SIRPαv1 allele). In a particular embodiment, the patient is homozygous for SIRPα and is SIRPαv1 / SIRPαv1. In a particular embodiment, the patient is heterozygous for SIRPα and is SIRPαv1 / SIRPαv2.

[0185] In a particular embodiment, the patient has at least one SIRPαv2 allele (i.e., the patient is homozygous and has two SIRPαv2 alleles, or is heterozygous for SIRPα and has one SIRPαv2 allele). In a particular embodiment, the patient is homozygous for SIRPα and is SIRPαv2 / SIRPαv2.

[0186] In another particular aspect of the invention, the uses and methods described herein are carried out in a combination therapy to render the patient sensitive to treatment with a second therapeutic agent (especially an immune checkpoint inhibitor or activator, more especially an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody), the anti-SIRPα antibody or its antigen-binding fragment being administered during a first time period or cycle, and the second therapeutic agent (especially an immune checkpoint inhibitor or activator, more especially an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody) being administered during a subsequent second time period or cycle; wherein the second therapeutic agent (especially an immune checkpoint inhibitor or activator, more especially an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody) is not administered during the first time period or cycle.

[0187] · Diagnostic and treatment methods

[0188] In one embodiment, the present invention relates to a method for determining whether a therapy for treating cancer is likely to be effective in a cancer patient, wherein the therapy comprises an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, particularly between human SIRPα and human CD47, and the method comprises:

[0189] - providing a biological sample previously obtained from the patient, particularly a blood sample, a plasma sample, a serum sample, a biopsy sample, and / or a tumor sample;

[0190] - determining or measuring the presence of myeloid cells expressing CD11b and SIRPα (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs, and / or tumor-associated neutrophils) in the biological sample;

[0191] - if myeloid cells expressing the CD11b and SIRPα biomarkers are present in the biological sample, the patient is likely to benefit from the treatment.

[0192] In a particular embodiment, when the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample exceeds 60%, particularly exceeds 65.3%, the patient is likely to have a positive response to treatment of their cancer by administration of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0193] In a preferred embodiment, an additional step of detecting the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly MDSCs) in a biological sample is performed. The presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs (particularly MDSCs) indicates that the patient may respond positively to treatment of their cancer by administration of the following combination: 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 as an immune checkpoint inhibitor, e.g., 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 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 such a case, the patient is classified as likely to respond positively to treatment of their cancer by administration of the following combination: a) an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound as an immune checkpoint inhibitor, e.g., a compound that inhibits the binding between PD-1 and PD-L1, preferably inhibits the binding between human PD-1 and human PD-L1 (particularly an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody, more 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).

[0194] The biological sample provided for performing the method is preferably a biopsy sample obtained from the tumor microenvironment. Markers expressed by myeloid cells can be detected by methods known in the art and as described above. CD11b and SIRPα can be detected in the biological sample by a method selected from the following: immunohistochemical analysis, immunoassay, gene expression profiling, fluorescence detection, enzyme activity assay, chemiluminescence detection, polymerase chain reaction, reverse transcription polymerase chain reaction, antibody binding, receptor binding array, target-specific primer extension, ELISA, radiolabeling.

[0195] In one aspect, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0196] (a) determining that the patient has cancer exhibiting a tumor microenvironment (TME) comprising myeloid cells expressing CD11b and SIRPα;

[0197] (b) Administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0198] In a particular embodiment, the determination in step (a) above is to detect myeloid cells expressing CD11b and SIRPα.

[0199] In one embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0200] (a) Selecting a patient having cancer that exhibits a tumor microenvironment (TME) comprising myeloid cells expressing CD11b and SIRPα;

[0201] (b) Administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0202] In one embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0203] (a) Determining that the patient has cancer that exhibits more than one characteristic, the characteristics including:

[0204] - At least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0205] (b) Administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0206] In a particular embodiment, the determination in step (a) above is to detect myeloid cells expressing CD11b and SIRPα.

[0207] In one embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0208] (a) Selecting a patient having cancer that exhibits more than one characteristic, the characteristics including:

[0209] - At least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0210] (b) Administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0211] The method or use of the present invention includes the step of administering to a patient in need of treatment an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47. The method may include the following final step: determining that the patient exhibits an improved outcome compared to the corresponding outcome observed in a reference patient to whom the anti-SIRPα antibody or an antigen-binding fragment thereof has been administered, wherein the reference patient has a cancer that does not exhibit the disclosed characteristics.

[0212] In one embodiment, the present invention relates to a method for treating cancer in a population of cancer patients in need thereof, the method comprising:

[0213] (a) Administering to a patient in a population of cancer patients an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient has a cancer that exhibits a tumor microenvironment (TME) comprising myeloid cells expressing CD11b and SIRPα;

[0214] (b) After administering the anti-SIRPα antibody or an antigen-binding fragment thereof, observing that the 15-month survival probability of patients with high SIRPα expression in the population of cancer patients is at least 0.45, and / or the 15-month survival probability of patients with low SIRPα expression is less than 0.17; or

[0215] After administering the anti-SIRPα antibody or an antigen-binding fragment thereof, observing that the 10-month survival probability of patients with high SIRPα expression in the population of cancer patients is at least 0.50, and / or the 10-month survival probability of patients with low SIRPα expression is less than 0.40; or

[0216] After administering the anti-SIRPα antibody or an antigen-binding fragment thereof, observing that the 20-month survival probability of patients with high SIRPα expression in the population of cancer patients is at least 0.25.

[0217] In a specific embodiment, the present invention relates to a method for treating a patient in need thereof, wherein the patient has been determined to have a cancer that exhibits more than one characteristic, the characteristics including:

[0218] - At least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0219] The method comprises: administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0220] 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 in which at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0221] The method comprises: administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0222] In another embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, wherein a tumor sample obtained from the patient has been determined to exhibit that at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα;

[0223] The method comprises: administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0224] In another embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0225] (a) selecting a patient having a tumor in which at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; and

[0226] (b) administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0227] In another embodiment, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising:

[0228] (a) detecting a sample of a cancer patient and determining whether it has more than one feature, the feature comprising:

[0229] - at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; and

[0230] (b) administering to the patient an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0231] In another embodiment, the present invention relates to a method for treating a cancer patient, the method comprising administering to the cancer patient an anti-SIRPα antibody or an antigen-binding fragment thereof, wherein the tumor of the cancer patient has more than one characteristic, the characteristics comprising:

[0232] - At least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα.

[0233] In another embodiment, the present invention relates to a method for classifying a human tumor, the method comprising:

[0234] (a) Detecting a sample from a human to detect the presence of myeloid cells expressing the biomarkers CD11b and SIRPα in the tumor microenvironment;

[0235] (b) Optionally, determining that at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells present in the tumor microenvironment express the biomarkers CD11b and SIRPα; and

[0236] (c) Identifying the tumor as a good candidate for treatment with an anti-SIRPα antibody or an antigen-binding fragment thereof.

[0237] In any embodiment of the treatment method disclosed herein, the method may further comprise the step of prescribing an anti-SIRPα antibody or an antigen-binding fragment thereof to a human.

[0238] In any embodiment of the treatment method 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, preferably an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody, more preferably an anti-PD-1 antagonist antibody.

[0239] In one embodiment of the method, the patient has been diagnosed with SIRPα-positive cancer, PD-1-positive cancer, or PD-L1-positive cancer, preferably cancer with solid tumors that express or overexpress SIRPα, PD-1, and / or PD-L1.

[0240] In any embodiment of the treatment method disclosed herein, the anti-SIRPα antibody or an antigen-binding fragment thereof inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47.

[0241] In any embodiment of the treatment method disclosed herein, the anti-SIRPα antibody or an antigen-binding fragment thereof may comprise:

[0242] i) A heavy chain variable domain comprising an amino acid sequence as shown in SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8; and

[0243] ii) A light chain variable domain comprising an amino acid sequence as shown in SEQ ID NO:9 or SEQ ID NO:10; or

[0244] i’) A heavy chain variable domain comprising:

[0245] - A heavy chain CDR1 (HCDR1) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No.15;

[0246] - A heavy chain CDR2 (HCDR2) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No.16 or SEQ ID No.17;

[0247] - A heavy chain CDR3 (HCDR3) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No.18, SEQ ID No.19, SEQ ID No.20 or SEQ ID No.21; and

[0248] ii’) A light chain variable domain comprising:

[0249] - A light chain CDR1 (LCDR1) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No.22;

[0250] - A light chain CDR2 (LCDR2) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No.23;

[0251] - A light chain CDR3 (LCDR3) domain comprising or consisting of an amino acid sequence as shown in SEQ ID No:24;

[0252] Wherein, preferably, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable domain comprising an amino acid sequence as shown in SEQ ID NO:8, and a light chain variable domain comprising an amino acid sequence as shown in SEQ ID NO:10.

[0253] In a specific embodiment of any of these treatment methods, the anti-SIRPα antibody or its antigen-binding fragment comprises:

[0254] i’) 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

[0255] 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;

[0256] iii’) a heavy chain variable domain comprising:

[0257] - a heavy chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.15;

[0258] - a heavy chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.17;

[0259] - a heavy chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.21; and

[0260] - a light chain variable domain comprising:

[0261] - a light chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.22;

[0262] - a light chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.23;

[0263] - a light chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.24.

[0264] In another embodiment of the therapeutic methods disclosed herein, the anti-SIRPα antibody or antigen-binding fragment thereof comprises an anti-SIRPa antibody as defined herein.

[0265] In a particular embodiment of the methods of treating a patient or cancer disclosed herein, the myeloid cells include tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils.

[0266] In one embodiment of the invention, there is provided a method of treating a cancer patient who may benefit from treatment with an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, wherein the patient is in need of treatment for cancer having solid tumors, the method comprising the steps of:

[0267] - Administering to a patient in need an effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47;

[0268] - wherein the patient has been determined to have myeloid cells expressing the CD11b and SIRPα biomarkers in the tumor microenvironment (TME).

[0269] The anti-SIRPα antibody or an antigen-binding fragment thereof can correspond to any anti-SIRPα antibody or antigen-binding fragment disclosed or cited herein, in particular:

[0270] · Comprising: a heavy-chain variable domain and a light-chain variable domain, the heavy-chain variable domain comprising the amino acid sequence shown in SEQ ID NO:8, and the light-chain variable domain comprising the amino acid sequence shown in SEQ ID NO:10; or

[0271] · Comprising:

[0272] A heavy-chain variable domain, the heavy-chain variable domain comprising:

[0273] - A heavy-chain CDR1 (HCDR1) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.15;

[0274] - A heavy-chain CDR2 (HCDR2) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.17;

[0275] - A heavy-chain CDR3 (HCDR3) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.21; and

[0276] - A light-chain variable domain, the light-chain variable domain comprising:

[0277] - A light-chain CDR1 (LCDR1) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.22; and

[0278] - A light-chain CDR2 (LCDR2) domain comprising or consisting of the amino acid sequence shown in SEQ ID No.23; and

[0279] - A light-chain CDR3 (LCDR3) domain comprising or consisting of the amino acid sequence shown in SEQ ID No:24; or

[0280] Comprising: a heavy chain comprising the amino acid sequence as shown in SEQ ID NO:11 and a light chain comprising the amino acid sequence as shown in SEQ ID NO:12, or a heavy chain comprising the amino acid sequence as shown in SEQ ID NO:13 and a light chain comprising the amino acid sequence as shown in SEQ ID NO:12.

[0281] The anti-SIRPα antibody or antigen-binding fragment may correspond to the anti-SIRPα antibody or antigen-binding fragment disclosed in the following published texts: WO2020 / 099653, WO2019 / 023347, WO2022 / 254379, WO2020 / 068752, WO2021 / 226576, WO2021174127, WO2019 / 226973, WO2018 / 190719, US20210347908, US20210347908, US20210347908, WO0066159, WO0140307, WO200140307, WO2009131453, WO2013056352, WO2014149477, WO2014186761, WO2015138600, WO2016063233, WO2016205042, WO2017178653, WO2018008470, WO2018026600, WO2018057669, WO2018107058, WO2018141964, WO2018160739, WO2018190719, WO2018210793, WO2019023347, WO2019183266, WO2019200462, WO2019226973, WO2020006374, WO2020013170, WO2020033646, WO2020068752, WO2020102422, WO2020099653, WO2020180811, WO2020247820, WO2021022044, WO2021032078, WO2021076908, WO2021129697, WO2021174127, WO2021185273, CN111635458, WO2021222746, WO2021226576, WO2021226591, CN113735973, CN111995682, CN112010979 or CN112574310, particularly corresponding to the anti-SIRPα antibody or antigen-binding fragment disclosed in any one of these published texts and cited herein.

[0282] In a particular embodiment of the method of treating a patient or a tumor disclosed herein, at least 55%, particularly at least 60%, preferably at least 65.3% of the myeloid cells (preferably tumor-associated macrophages, monocytes, MDSCs, myeloid dendritic cells, and / or tumor-associated neutrophils) present in the tumor microenvironment of the patient express the biomarkers CD11b and SIRPα.

[0283] In a particular embodiment of the method of treating a patient or a tumor disclosed herein, the tumor microenvironment of the patient has tumor-associated macrophages, monocytes, myeloid dendritic cells, tumor-associated neutrophils, and / or MDSCs, particularly MDSCs.

[0284] In a particular embodiment of the method of treating a patient or a tumor disclosed herein, the patient has a liquid or solid cancer, preferably a cancer with advanced solid tumors, more particularly adrenocortical carcinoma, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer (particularly triple-negative breast cancer), lung cancer (particularly non-small cell lung cancer (NSCLC)), cervical cancer, or colorectal cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer, or colorectal cancer.

[0285] In another embodiment, the present invention relates to a method of treating a patient with cancer, wherein the patient has been diagnosed with cancer, and the method comprises the following steps:

[0286] - providing a biological sample previously obtained from the patient, particularly a blood sample, plasma sample, serum sample, biopsy sample, and / or tumor sample, more particularly a biological sample previously obtained from the patient and the sample is from the tumor (TME) microenvironment of the patient and contains myeloid cells, particularly, the sample is a biopsy sample of the tumor microenvironment of the patient;

[0287] - measuring the presence of myeloid cells (particularly tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs, and / or tumor-associated neutrophils) expressing CD11b and SIRPα in the biological sample;

[0288] - when the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample exceeds 60%, particularly exceeds 65.3%, administering to the patient a therapeutically effective amount of an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding of SIRPα to SIRPα, preferably human SIRPα to human CD47.

[0289] In a particular embodiment, the present invention relates to a method for treating cancer in a patient, wherein the patient has been diagnosed with cancer, the method comprising the steps of:

[0290] - providing a biological sample previously obtained from the patient, in particular a blood sample, a plasma sample, a serum sample, a biopsy sample and / or a tumor sample;

[0291] - measuring the presence of myeloid cells expressing CD11b and SIRPα (in particular tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils) in the biological sample;

[0292] - optionally measuring the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, myeloid-derived suppressor cells (MDSCs) and / or tumor-associated neutrophils (in particular MDSCs) in the biological sample;

[0293] - when the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample exceeds 65.3%, and when tumor-associated macrophages, monocytes, myeloid dendritic cells, myeloid-derived suppressor cells (MDSCs) and / or tumor-associated neutrophils (in particular MDSCs) are detected in the sample, administering to the patient a combination therapy comprising: a) an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding of SIRPα to CD47, preferably human SIRPα to human CD47, and b) a compound that inhibits the binding of PD-1 to PD-L1, preferably human PD-1 to human PD-L1, in particular an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody, more particularly an anti-PD-1 antagonist antibody.

[0294] In a particular embodiment, the patient has cancer with solid tumors, in particular cancer with advanced solid tumors. In another embodiment, the present invention relates to a method for treating cancer in a patient, wherein the patient is treated for: ovarian cancer, pancreatic cancer, cancer of the ampulla of Vater, microsatellite stable (MSS) cancer, microsatellite unstable (MSI) cancer, colorectal cancer (in particular MSI and MSS colorectal cancer), fibrolamellar carcinoma, breast cancer, endocrine adenocarcinoma, hepatocellular carcinoma, melanoma, renal cancer, lung cancer (in particular non-small cell lung cancer (NSCLC)), head and neck cancer (in particular head and neck squamous cell carcinoma (HNSCC)), gastric cancer and hepatocellular carcinoma.

[0295] In another embodiment, the present invention relates to a method for treating cancer in a patient, wherein the patient is diagnosed with SIRPα-positive cancer, PD-1-positive cancer or PD-L1-positive cancer, in particular cancer with solid tumors that expresses or overexpresses SIRPα, PD-1 and / or PD-L1.

[0296] In another embodiment, the present invention relates to a method for treating cancer in a patient who has not previously been 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).

[0297] In another embodiment, the present invention relates to a method for treating cancer in a patient who has not been treated with an anti-SIRPα antibody prior to use.

[0298] In another embodiment, the present invention relates to a method for treating cancer in a patient who has shown disease progression in response to a 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).

[0299] In another embodiment, the present invention relates to a method for sensitizing a cancer patient to treatment with an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody, wherein an anti-SIRPα antibody or an antigen-binding fragment thereof is administered during a first time period and an anti-PD-1 antagonist antibody or an anti-PD-L1 antibody is administered during a subsequent second time period, and wherein the anti-PD-1 antagonist antibody or the anti-PD-L1 antibody is not administered during the first time period.

[0300] In another embodiment, the present invention relates to a method for treating cancer in a patient, wherein the anti-SIRPα antibody or an antigen-binding fragment thereof comprises:

[0301] i) a heavy chain variable domain comprising an amino acid sequence as shown in SEQ ID No: 3, SEQ ID No: 4, SEQ ID No: 5, SEQ ID No: 6, SEQ ID No: 7 or SEQ ID No: 8; and

[0302] a light chain variable domain comprising an amino acid sequence as shown in SEQ ID No: 9 or SEQ ID No: 10.

[0303] ii) a heavy chain variable domain comprising:

[0304] a. a heavy chain CDR1 (HCDR1) domain comprising an amino acid sequence as shown in SEQ ID No: 15 or consisting thereof; and

[0305] b. a heavy chain CDR2 (HCDR2) domain comprising an amino acid sequence as shown in SEQ ID No: 16 or SEQ ID No: 17 or consisting thereof; and

[0306] c. The heavy chain CDR3 (HCDR3) domain, comprising or consisting of the amino acid sequence as shown in SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20 or SEQ ID No. 21; and

[0307] The light chain variable domain, which comprises:

[0308] a. The light chain CDR1 (LCDR1) domain, comprising or consisting of the amino acid sequence as shown in SEQ ID No. 22;

[0309] b. The light chain CDR2 (LCDR2) domain, comprising or consisting of the amino acid sequence as shown in SEQ ID No. 23;

[0310] c. The light chain CDR3 (LCDR3) domain, comprising or consisting of the amino acid sequence as shown in SEQ ID No. 24.

[0311] In particular, the anti-SIRPα antibody or its antigen-binding fragment comprises: a heavy chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 8 and a light chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 10.

[0312] In another embodiment, the present invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody or its antigen-binding fragment, the anti-SIRPα antibody or its antigen-binding fragment comprising: a heavy chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 8 and a light chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 10.

[0313] In another embodiment, the present invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody, the anti-SIRPα antibody comprising: a heavy chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 8 and a light chain variable domain comprising the amino acid sequence as shown in SEQ ID No: 10.

[0314] In another embodiment, the present invention relates to a method for treating cancer in a patient by administering an anti-SIRPα antibody or its antigen-binding fragment, the anti-SIRPα antibody or its antigen-binding fragment comprising: a heavy chain comprising the amino acid sequence as shown in SEQ ID No: 11 and a light chain comprising the amino acid sequence as shown in SEQ ID No: 12.

[0315] In another embodiment, the present invention relates to a method of treating cancer in a patient by administering an anti-SIRPα antibody, the anti-SIRPα antibody comprising: a heavy chain comprising the amino acid sequence as shown in SEQ ID No: 13 and a light chain comprising the amino acid sequence as shown in SEQ ID No: 12.

[0316] Examples

[0317] Materials and methods

[0318] Treatment outcomes (such as overall survival (OS) and progression-free survival (PFS)) were collected from the iCRF (case report form) files.

[0319] Serial staining was performed by immunohistochemistry (IHC) using Veracyte technology and Leica Bond RX to evaluate target features such as CD47 expression in tumor cells at baseline, SIRPα expression in CD11b+ myeloid cells, etc. Each tissue section was scanned with Nanozoomer XR / x20.

[0320] Based on the comparison of the expression levels of these features with the median expression of the study population, samples before treatment were divided into a high-expression group or a low-expression group.

[0321] Survival was evaluated using the Kaplan Meier curve and calculated using the survival R package. The statistical test used was the log-rank test for comparing the survival of the high-expression group and the low-expression group. The hypothesis addressed by the log-rank test is that there is no difference in the probability of event occurrence between the populations studied at any time point, and when the p-value < 0.05, the difference is considered significant.

[0322] Example 1 – Expression of CD47, SIRPα, and CD11b in tumor cells and immune cells from the tumor microenvironment (TME) of cancer patients and CD11b.

[0323] The baseline status of the patients has been evaluated to determine biomarkers that respond to the anti-SIRPα antibody or its antigen-binding fragment.

[0324] Figure 1It is shown that classifying patients according to the overall expression of CD47 in tumor cells cannot distinguish patients who benefit from treatment with an anti-SIRPα antibody in terms of overall survival from patients who do not benefit from such treatment despite receiving the same antibody. Whether the patient receives monotherapy with an anti-SIRPα antibody or combination therapy with an anti-SIRPα antibody and a PD-1 inhibitor, assessing the expression of CD47 in tumor cells is not applicable to assessing whether a patient is likely to benefit from monotherapy or combination therapy with an anti-SIRPα antibody (especially combination therapy with a PD-1 inhibitor).

[0325] Figure 2 It is shown that classifying patients according to the overall expression of SIRPα in tumor cells cannot distinguish patients who benefit from treatment with an anti-SIRPα antibody in terms of overall survival from patients who do not benefit from such treatment despite receiving the same antibody. Whether the patient receives monotherapy with an anti-SIRPα antibody or combination therapy with an anti-SIRPα antibody and a PD-1 inhibitor, assessing the expression of SIRPα in tumor cells is not applicable to assessing whether a patient is likely to benefit from monotherapy or combination therapy with an anti-SIRPα antibody (especially combination therapy with a PD-1 inhibitor).

[0326] Figure 3 shows that classifying patients according to the presence of CD11b+SIRPα+ myeloid cells in the tumor microenvironment can distinguish patients who benefit from treatment with an anti-SIRPα antibody (i.e., those with disease regression, no progression, or slower progression) from patients who do not benefit from such treatment despite receiving the same antibody. As shown in Figures 3A and 3B, patients with CD11b+SIRPa+ myeloid cells of at least 65.3% had longer survival times compared to patients with CD11b+SIRPα+ myeloid cells below 65.3%: 25% of patients with CD11b+SIRPa+ myeloid cells of at least 65.3% were still alive after 30 months of treatment. This method of classifying patients was effective when patients received monotherapy with an anti-SIRPα antibody and when patients received combination therapy with an anti-SIRPα antibody, especially combination therapy with a PD-1 inhibitor.

[0327] Figures 3C, 3D, 3E, and 3F show that patients with at least 60% (Figures 3C and 3D) or 55% (Figures 3E and 3F) CD11b+SIRPα+ myeloid cells had longer survival times compared to patients with less than 60% or 55% CD11b+SIRPα+ myeloid cells: 25% of patients with at least 60% or 55% CD11b+SIRPα+ myeloid cells were still alive after 20 months of treatment. This patient classification was effective both when patients were treated with anti-SIRPα antibody monotherapy and when patients were treated with anti-SIRPα antibody combination therapy, particularly in combination with a PD-1 inhibitor. Among patients receiving anti-SIRPα antibody monotherapy or combination therapy, the overall survival curve of patients with more than 65.3% CD11b+SIRPα+ myeloid cells declined more slowly compared to the overall survival curve of patients with more than 60% or 55% CD11b+SIRPα+ myeloid cells. After 20 months of treatment, the overall survival probability of patients with more than 65.3% CD11b+SIRPα+ myeloid cells was higher than that of patients with a lower percentage of CD11b+SIRPα+ myeloid cells.

[0328] Furthermore, the overall survival curve of patients with more than 65.3% CD11b+SIRPα+ myeloid cells declined more slowly compared to the overall survival curve of patients with less than 60% CD11b+SIRPα+ myeloid cells.

[0329] Figure 4 showed that the gene expression profile of immune cells present in the tumor microenvironment of patients who received combination therapy with an anti-SIRPα antibody and a PD-1 inhibitor and who had a positive response to the treatment was similar to the gene expression profile of MDSCs. Thus, these results suggest 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 PD-1 inhibitor.

[0330] This predictive result is particularly favorable for combination therapies that include the administration of an anti-SIRPα antibody and an anti-PD-1 inhibitor.

Claims

1. Use of a composition for treating cancer in a patient, wherein, The cancer is characterized in that the tumor microenvironment (TME) contains myeloid cells expressing CD11b and SIRPα, and at least 55%, particularly at least 60%, more particularly at least 65.3% of the myeloid cells present in the patient's TME before and / or during treatment express CD11b and SIRPα; the composition comprises an anti-SIRPα compound that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, particularly an anti-SIRPα antibody or an antigen-binding fragment thereof.

2. The composition for use according to claim 1, wherein, The myeloid cells from the TME are obtained from a biological sample previously obtained from the patient's TME.

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

4. The composition for use according to claim 1 or 2, wherein, The patient's tumor microenvironment has myeloid cells.

5. The composition for use according to any one of claims 1 to 4, for treating a patient suffering from a liquid cancer or a solid cancer, particularly a cancer with advanced solid tumors, more particularly adrenocortical carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer, particularly triple-negative breast cancer, lung cancer, particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer.

6. The composition for use according to any one of claims 1 to 5, wherein, The composition is administered in combination therapy with an immune checkpoint inhibitor that interacts between tumor cells and myeloid cells, particularly in combination therapy with a compound selected from: 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, more particularly in combination therapy with 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 in combination therapy with a compound targeting lymphocyte activation gene-3 (LAG-3), particularly an antibody against lymphocyte activation gene-3.

7. The composition for use according to claim 5 or 6, wherein, The patient is diagnosed with SIRPα-positive cancer, PD-1-positive cancer or PD-L1-positive cancer, preferably a cancer with solid tumors expressing or overexpressing 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 composition for use according to any one of claims 1 to 8, wherein, The anti-SIRPα antibody or antigen-binding fragment thereof comprises: a. a heavy chain variable domain comprising an amino acid sequence as shown in SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7 or SEQ ID No:8; and b. a light chain variable domain comprising an amino acid sequence as shown in SEQ ID No:9 or SEQ ID No:10, Preferably, the anti-SIRPα antibody or antigen-binding fragment thereof comprises: a heavy chain variable domain comprising the amino acid sequence as shown in SEQ ID No:8 and a light chain variable domain comprising the amino acid sequence as shown in SEQ ID No:

10.

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

12.

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

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

13. The method according to claim 11 or 12, wherein, When the percentage of myeloid cells expressing CD11b and SIRPα in the biological sample is at least 55%, particularly at least 60%, the patient may respond positively to treatment of their cancer by administration of an anti-SIRPα antibody or antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably human SIRPα and human CD47.

14. The method according to any one of claims 11 to 13, wherein, The patient has liquid cancer or solid cancer, particularly cancer with advanced solid tumors, more particularly adrenocortical carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastrointestinal cancer, head and neck cancer, kidney 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, more particularly ovarian cancer, breast cancer, particularly triple-negative breast cancer, lung cancer, more particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer, most particularly non-small cell lung cancer (NSCLC), cervical cancer or colorectal cancer.

15. The method according to any one of claims 11 to 14, the method further comprising the step of detecting the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, particularly MDSCs, in a biological sample, the presence of tumor-associated macrophages, monocytes, myeloid dendritic cells, MDSCs and / or tumor-associated neutrophils, particularly MDSCs, indicating that the patient may respond positively to treatment of their cancer by administration of the following combination: a) an anti-SIRPα antibody or an antigen-binding fragment thereof that inhibits the binding between SIRPα and CD47, preferably between human SIRPα and human CD47, and b) a compound as an immune checkpoint inhibitor, 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 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.

16. The method according to any one of claims 11 to 15, wherein The patient may respond positively to treatment of their cancer by administration of the following combination: a) an anti-SIRPα antibody or an 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-PD-1 antagonist antibody, more 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. The method according to any one of claims 11 to 16, wherein CD11b and SIRPα in the biological sample are detected by a method selected from the following: immunoassay, particularly immunohistochemistry, gene expression profiling, fluorescence detection, enzyme activity assay, chemiluminescence detection, polymerase chain reaction, reverse transcription polymerase chain reaction, antibody binding, receptor binding array, target-specific primer extension, ELISA, radiolabeling.

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