Methods of using inflammatory markers to guide anti-CLEVER-1 cancer therapy

Abstract

A method for selecting a patient for anti-CLEVER-1 therapy prior to initiating anti-CLEVER-1 therapy using one or several of the inflammatory markers selected from interferon gamma (IFNγ), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and C-reactive protein. If the measured level of the inflammatory marker is substantially within the reference value of the inflammatory marker or lower than the average reference value of the inflammatory marker, it is an indication for selecting the patient and initiating anti-CLEVER-1 therapy.

Description

[Technical field]

[0001] The present invention relates to the use of one or more inflammatory markers to guide anti-CLEVER-1 based cancer therapy, and to methods for selecting patients for anti-CLEVER-1 therapy prior to anti-CLEVER-1 therapy. [Background technology]

[0002] Anti-PD-1, anti-PD-L1, and anti-CTLA-4 immune checkpoint inhibitors are widely used in clinical patient care. Currently, immune checkpoint inhibitors targeting CTLA-4 and the PD-1 / PD-L1 axis have been approved for clinical use and are highly effective in approximately 10-20% of patients with melanoma and certain other tumors, but several other important cancer types (e.g., prostate, breast, and colorectal cancer) remain refractory to them, and no clear biomarkers are available that could distinguish responders from nonresponders and guide treatment [1]. Patients who respond well to checkpoint blockade usually have a high density of interferon gamma (IFNg)-producing CD8+ cells. + Tumors that do not respond to immune checkpoint blockade have a pre-existing antitumor immune response characterized by T cells, expression of PD-L1 on tumor-infiltrating immune cells, and high mutational burden. Tumors that do not respond to immune checkpoint blockade exhibit either a stromal T cell phenotype, in which infiltration of T cells into the tumor (TIL) or activation of T cells in the tumor microenvironment (TME) is prevented by an immunosuppressive stromal compartment, or a noninflammatory phenotype, characterized by low T cell infiltration, low mutational burden, and high proliferation of tumor cells. Tumors can be immunologically classified (inflammatory vs. noninflammatory) based on the presence of tumor-infiltrating cytotoxic CD8 T cells [2]. Inflammatory tumors show high mutational burden, high IFNg and PD-L1 expression, and respond well to immune checkpoint blockade therapy. IFNg produced by T cells is considered necessary for immunological checkpoint inhibitors to function as anticancer drugs.

[0003] However, innate immune cells such as macrophages can suppress T cell activation and contribute to tumor progression, despite their high mutational burden. Macrophages, which contribute to tumor-associated immune suppression and provide signals that support tumor growth, may be highly eligible candidates for targeted therapy because these cells are abundant in a variety of tumors, are highly plastic, and can transform into pro-inflammatory macrophages that support T cell activation and tumor rejection [3, 4]. To date, macrophage-targeting strategies in clinical development utilize inhibition of macrophage colony-stimulating factor receptors to deplete macrophage populations in tumors [5]. However, resistance to these approaches has already been reported [6]. Thus, there is a need to find novel ways to utilize these cells to trigger tumor cell killing by the immune system.

[0004] In recent years, increasing attention has been paid to the contribution of scavenger receptors in regulating macrophage responses to different stimuli. CLEVER-1 (also known as STABILIN-1) is a multifunctional molecule that confers scavenging capacity to a subset of anti-inflammatory macrophages [7, 8]. In these cells, it is involved in receptor-mediated endocytosis and recycling, intracellular sorting, and transcytosis of altered and normal self-components. More recently, the role of Stab1 in several tumor models has been demonstrated. - / - Growth and metastasis have been found to be attenuated in Clever-1 knockout (Clever-1) mice and in mice treated with anti-CLEVER-1 therapy [9, 10]. In addition, combination treatment with anti-CLEVER-1 agents together with anti-PD-1 agents has been shown to generate anti-tumor responses in mouse models of triple-negative breast and colon cancer

[10] . The first anti-CLEVER-1 antibody, named bexmarilimab, has entered clinical development and has shown promising anti-tumor responses in its first-in-human trials

[11] . Summary of the Invention

[0005] Now, surprisingly, in contrast to classical checkpoint inhibitors, anti-PD-1, anti-PD-L1, and anti-CTLA-4, anti-CLEVER-1 therapy has been found to be effective in non-inflammatory tumor types characterized by low interferon gamma (IFNg) levels as well as low levels of other inflammatory cytokines. Recently, about 30% of patients with advanced melanoma, gastric cancer, and cholangiocarcinoma have been found to respond well to the anti-CLEVER-1 IgG4 antibody bexmarilimab (FP-1305) in a phase I / II study (clinicaltrials.gov NCT03733990: A Study to Evaluate Safety, Tolerability and Preliminary Efficacy of FP-1305 in Cancer Patients (MATINS)). It has now been further observed that those patients who respond to anti-CLEVER-1 antibody therapy in the MATINS study can be effectively identified by low IFNg values ​​compared to high values ​​at baseline, which is in complete contrast to what has been seen so far in the field of immuno-oncology. Similarly, it has been observed that tumor necrosis factor alpha (TNF-α) levels in serum samples are low at baseline or are substantially the same as reference values ​​in patients who experienced clinical benefit in the MATINS study. In addition, based on receiver operating characteristic (ROC) curve analysis, it is expected that 83% of patients with low levels of IFNg and TNF-α will experience clinical benefit when treated with the anti-CLEVER-1 antibody bexmarilimab. Furthermore, when classical pro-inflammatory cytokines such as interleukin 6 (IL-6) and / or interleukin 8 (IL-8) are added to the ROC analysis, the likelihood of predicting response to the anti-CLEVER-1 antibody bexmarilimab increases to 91%. It has also been observed that the standard inflammatory test C-reactive protein (CRP) has a good ability to reflect non-inflammatory cancer types that respond to the anti-CLEVER-1 antibody bexmarilimab.

[0006] Thus, the present invention provides a novel inflammatory marker-based therapy for cancer patients, thus reducing or even eliminating the above-mentioned problems in defining non-responders from responding patients. The present invention offers the possibility to probe the molecular landscape of solid tumors via a simple blood draw.

[0007] The present invention is based on measuring one or more inflammatory markers before starting anti-CLEVER-1 therapy to select patients who should receive anti-CLEVER-1 therapy, in particular to select patients who will benefit from receiving anti-CLEVER-1 therapy, including administration of an agent capable of binding to CLEVER-1, preferably an anti-CLEVER-1 antibody, more preferably the anti-CLEVER-1 antibody bexmarilimab. The present invention provides a tool for selecting those who should receive anti-CLEVER-1 therapy, preferably anti-CLEVER-1 antibody therapy, more preferably anti-CLEVER-1 antibody bexmarilimab therapy. The present invention provides the use of one or more inflammatory markers selected from the group consisting of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and C-reactive protein (CRP) to induce anti-CLEVER-1 based cancer therapy.

[0008] An exemplary method according to the present invention for selecting a patient for anti-CLEVER-1 therapy, prior to initiating the anti-CLEVER-1 therapy, the anti-CLEVER-1 therapy comprising administration of an agent capable of binding to CLEVER-1 in the patient, preferably an anti-CLEVER-1 antibody, more preferably the anti-CLEVER-1 antibody bexmarilimab, the method comprising the following steps: - providing a blood sample obtained from the patient at a first time point prior to initiating anti-CLEVER-1 therapy; - measuring from the obtained sample the level of one or more inflammatory markers selected from the group consisting of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP); - comparing the measured level of an inflammatory marker with a reference value for said inflammatory marker; wherein a measured level of the inflammatory marker that is substantially within the reference value for the inflammatory marker or lower than the average reference value for the inflammatory marker is an indication for selecting the patient and initiating anti-CLEVER-1 therapy.

[0009] The method according to the present invention may include the measurement of only one inflammatory marker selected from the group consisting of IFNg, TNF-α, IL-6, IL-8, and CRP, but may also be a combination of two or more of these inflammatory markers. To decide to start anti-CLEVER-1 therapy, these inflammatory markers must be at baseline or below baseline, or substantially the same as or lower than the reference value of the inflammatory marker. If the level of the inflammatory marker is abnormally high compared to the baseline, it may lead to non-responsiveness to anti-CLEVER-1 therapy, for example, anti-CLEVER-1 antibody therapy, such as anti-CLEVER-1 antibody bexmarilimab therapy.

[0010] Furthermore, the present invention provides a method for treating a cancer patient, the method comprising at least the following steps: - obtaining a blood sample from a cancer patient at a first time point prior to initiating anti-CLEVER-1 therapy; - measuring from the obtained sample the level of one or more inflammatory markers selected from the group consisting of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP); - comparing the measured level of an inflammatory marker with a reference value for said inflammatory marker; - initiating administration of an agent capable of binding to CLEVER-1, preferably an anti-CLEVER-1 antibody, more preferably the anti-CLEVER-1 antibody bexmarilimab, in the patient when the measured level of the inflammatory marker is substantially within the baseline value of the inflammatory marker or lower than the average baseline value of the inflammatory marker.

[0011] According to the present invention, an agent capable of binding to CLEVER-1, preferably an anti-CLEVER-1 antibody, more preferably the humanized monoclonal immunoglobulin G4 κ antibody bexmarilimab, can be efficiently used for the treatment of cancer in cancer patients, in particular for the treatment of advanced solid tumors. In one aspect of the present invention, an anti-CLEVER-1 antibody, preferably the humanized monoclonal immunoglobulin G4 κ antibody bexmarilimab, is used for the treatment of cancer, preferably for the treatment of advanced solid tumors in patients who are within or exhibit lower than average baseline values ​​of inflammatory markers prior to the initiation of anti-CLEVER-1 therapy, the inflammatory markers comprising interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and / or C-reactive protein (CRP). [Brief description of the drawings]

[0012] [Figure 1] Inflammatory marker data extracted from the expansion cohort of the First-in-Human Bexumarilimab Trial (MATINS) show that subjects who showed clinical benefit from bexumarilimab in Kaplan-Meier survival analysis (survival probability 0.8 in Figure 1) had significantly lower baseline serum IFNg (Figure 2) and TNF-α levels (Figure 3). In Figures 2 and 3, the right panel presents subjects who benefit from bexumarilimab in Kaplan-Meier survival analysis (Disease Control Rate (DCR) = yes). [Diagram 2]Inflammatory marker data extracted from the expansion cohort of the First-in-Human Bexumarilimab Trial (MATINS) show that subjects who showed clinical benefit from bexumarilimab in Kaplan-Meier survival analysis (survival probability 0.8 in Figure 1) had significantly lower baseline serum IFNg (Figure 2) and TNF-α levels (Figure 3). In Figures 2 and 3, the right panel presents subjects who benefit from bexumarilimab in Kaplan-Meier survival analysis (Disease Control Rate (DCR) = yes). [Diagram 3] Inflammatory marker data extracted from the expansion cohort of the First-in-Human Bexumarilimab Trial (MATINS) show that subjects who showed clinical benefit from bexumarilimab in Kaplan-Meier survival analysis (survival probability 0.8 in Figure 1) had clearly lower baseline serum IFNg (Figure 2) and TNF-α levels (Figure 3). In Figures 2 and 3, the right panel presents subjects who benefit from bexumarilimab in Kaplan-Meier survival analysis (Disease Control Rate (DCR) = yes). [Figure 4] ROC analysis comparing pretreatment IFNg and TNF-α levels in patients who gained survival benefit from bexmarilimab with those who did not in the First-in-Human Bexumarilimab Trial (MATINS). Low IFNg and TNF-α values ​​are associated with clinical benefit. The predictive value of these biomarkers was excellent (AUC 0.83, p<0.0001). [Diagram 5] ROC analysis comparing pretreatment IFNg, TNFa, IL-6, and IL-8 levels in patients who gained survival benefit from bexmarilimab with those who did not in the First-in-Human Bexumarilimab Trial (MATINS). Lower values ​​are associated with clinical benefit. The predictive value of these biomarkers was excellent (AUC 0.91, p<0.0001). [Figure 6]ROC analysis comparing pretreatment CRP levels in patients who gained survival benefit from bexmarilimab with those who did not in the First-in-Human Bexumarilimab Trial (MATINS). Lower CRP values ​​are associated with clinical benefit. The predictive value of CRP alone is relatively good (AUC 0.78, p=0.036). [Figure 7] Amino acid sequences of the light and heavy chains of the anti-CLEVER-1 antibody bexmarilimab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] CLEVER-1 is a protein disclosed in WO 03 / 057130, Common Lymphatic Endothelial and Vascular Endothelial Receptor-1. It is a binding protein that mediates lymphocyte adhesion to endothelium in both the systemic vascular and lymphatic systems. By blocking the interaction of CLEVER-1 and its lymphocyte substrates, it is possible to simultaneously control lymphocyte recirculation and lymphocyte migration at the sites of lymphocyte inflow and outflow into and out of tissues, as well as associated conditions such as inflammation.

[0014] The term "agent capable of binding to CLEVER-1" refers to agents including antibodies and fragments thereof, peptides or equivalents capable of binding to CLEVER-1 to block the interaction of CLEVER-1 and malignant tumor cells. The agent may also be any other inhibitor, such as a small molecule inhibitor or a macromolecule, that binds to the CLEVER-1 receptor and has sufficient affinity to inhibit protein activity. The term "antibody or fragment thereof" is used in the broadest sense to encompass antibodies or fragments thereof capable of binding to the CLEVER-1 molecule in an individual. In particular, this shall be understood to include chimeric, humanized or primatized antibodies, as well as antibody fragments and single chain antibodies (e.g., Fab, Fv), so long as they exhibit the desired biological activity. Particularly useful agents are anti-CLEVER-1 antibodies and fragments thereof. Thus, according to one embodiment of the present invention, the agent capable of binding to CLEVER-1, i.e., the anti-CLEVER-1 agent, is selected from the group consisting of antibodies or fragments thereof, peptide(s), macromolecules, and any combination thereof. According to the present invention, "anti-CLEVER-1 treatment" or "anti-CLEVER-1 therapy" refers to a treatment comprising the administration of at least one agent capable of binding to CLEVER-1, preferably an anti-CLEVER-1 antibody. In a preferred embodiment of the present invention, anti-CLEVER-1 therapy refers to an anti-CLEVER-1 antibody therapy.

[0015] According to one embodiment of the invention, the anti-CLEVER-1 antibody is a therapeutic humanized anti-CLEVER-1 antibody. According to one embodiment of the invention, the anti-CLEVER-1 antibody is a humanized monoclonal CLEVER-1 antibody previously presented in WO 2017 / 182705.

[0016] In one embodiment of the invention, the anti-CLEVER-1 antibody is the humanized monoclonal immunoglobulin G4 κ antibody bexmarilimab (International Nonproprietary Name (INN) as disclosed in WHO Drug Information, Vol. 33, No. 4, pages 814-815 (2019)), or a bexmarilimab variant or a bexmarilimab biosimilar. As used herein, "bexmarilimab" refers to a humanized monoclonal IgG4 antibody having the structure as set out in WHO Drug Information, Vol. 33, No. 4, pages 814-815 (2019). The humanized IgG4 monoclonal anti-CLEVER-1 antibody bexmarilimab comprises the amino acid sequence SEQ ID NO:1 of the heavy chain and the amino acid sequence SEQ ID NO:2 of the light chain. The amino acid sequences of the heavy chain (SEQ ID NO:1) and light chain (SEQ ID NO:2) of the anti-CLEVER-1 antibody bexmarilimab are also shown in FIG. 7.

[0017] Bexmarilimab biosimilar refers to a biological product approved by a regulatory agency in any country for marketing as a bexmarilimab biosimilar. In one embodiment, the bexmarilimab biosimilar contains a bexmarilimab variant as a drug substance. In one embodiment, the bexmarilimab biosimilar has heavy and light chains of substantially the same amino acid sequences as bexmarilimab. As used herein, "bexmarilimab variant" refers to an antibody that comprises the same heavy and light chain sequences as bexmarilimab, except that it has one or more conservative amino acid substitutions at positions located outside the light chain CDRs and / or one or more conservative amino acid substitutions located outside the heavy chain CDRs, e.g., the variant positions are located in the framework or constant regions. In other words, bexmarilimab and bexmarilimab variants contain the same CDR sequences, but differ from each other due to having conservative amino acid substitutions at other positions in their full-length light and heavy chain sequences. The bexmarilimab variants are substantially identical to bexmarilimab in terms of binding affinity to CLEVER-1.

[0018] According to one embodiment of the invention, a cell line producing the therapeutic anti-CLEVER-1 antibody bexmarilimab (FP-1305) has been deposited under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure at the DSMZ-German Collection of Microorganisms and Cell Cultures GmbH, Inhoffenstrasse 7B, D-38124 Braunschweig, Germany, on May 27, 2020, and has the accession number DSM ACC3361. The deposited embodiment is intended as a single illustration of one aspect of the invention, and the invention is not limited in scope by the deposited culture, since any culture that is functionally equivalent is within the scope of the invention. The submission of material herein does not constitute an admission that the written description contained herein is insufficient to enable the practice of any aspect of the invention, including its best mode, and should not be construed as limiting the scope of the claims to the specific exemplifications it represents.

[0019] According to one embodiment of the invention, a sample obtained at a first time point prior to administration of an agent capable of binding to CLEVER-1, preferably prior to administration of an anti-CLEVER-1 antibody, such as the anti-CLEVER-1 antibody bexumalimab, to a patient refers to a sample obtained prior to the first administration of an agent capable of binding to CLEVER-1, preferably prior to the first administration of an anti-CLEVER-1 antibody, such as the anti-CLEVER-1 antibody bexumalimab. A sample obtained from a patient refers to a blood sample.

[0020] According to one embodiment of the present invention, the method comprises measuring one or more inflammatory markers selected from the group consisting of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), or C-reactive protein (CRP) from the obtained sample, and using the measurement of one inflammatory marker or a combination of measurements of two or more inflammatory markers to select to treat the patient with an anti-CLEVER-1 therapy, preferably an anti-CLEVER-1 antibody therapy. The levels of the inflammatory markers can be measured from serum and / or plasma. To decide to start an anti-CLEVER-1 therapy, preferably an anti-CLEVER-1 antibody therapy, the levels of these inflammatory markers should be in the average range of the baseline of inflammatory markers or lower than the average baseline value. Based on the findings of the present invention, abnormally high values ​​of the inflammatory markers compared to the baseline value may lead to non-responsiveness to an agent capable of binding to CLEVER-1, for example the anti-CLEVER-1 antibody bexmarilimab. Based on the present invention, only one inflammatory marker can be used for decision-making to initiate anti-CLEVER-1 therapy, preferably anti-CLEVER-1 antibody therapy, whereas when a combination of two or more inflammatory markers is used, the confidence of the likely response to therapy is increased.

[0021] According to one embodiment of the invention, the method comprises measuring the levels of at least interferon gamma (IFNg) and tumor necrosis factor alpha (TNF-α). In one embodiment of the invention, the method comprises measuring the levels of interferon gamma (IFNg) and / or tumor necrosis factor alpha (TNF-α) and also the levels of interleukin 6 (IL-6) and / or interleukin 8 (IL-8). In one embodiment of the invention, the method comprises measuring the levels of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and / or interleukin 8 (IL-8) in combination with measuring the level of C-reactive protein (CRP). According to one embodiment of the invention, the level of C-reactive protein (CRP) alone may be used to assess the need to start an anti-CLEVER-1 therapy, preferably an anti-CLEVER-1 antibody therapy.

[0022] According to the present invention, the measurement of inflammatory markers can be carried out by conventional methods known in the art. For these purposes, various analytical methods and devices are available. The reference or baseline value of an inflammatory marker depends on the measurement method. According to the present invention, the reference or baseline value of an inflammatory marker means a normal value or a value within a certain range that is defined in the art as being the normal or average conventional value of said inflammatory marker.

[0023] According to one embodiment of the present invention, anti-CLEVER-1 therapy comprises the administration of a therapeutically effective amount of an agent capable of binding to Clever-1, preferably an anti-CLEVER-1 antibody, more preferably the anti-CLEVER-1 antibody bexumalimab. The terms "therapy", "treatment" or "treating" shall be understood to include complete cure of a disease or disorder as well as amelioration or alleviation of said disease or disorder. In one embodiment according to the present invention, anti-CLEVER-1 therapy refers to anti-CLEVER-1 antibody therapy comprising the administration of a therapeutically effective amount of an anti-CLEVER-1 antibody, preferably the anti-CLEVER-1 antibody bexumalimab. The term "therapeutically effective amount" is meant to include any amount of an agent according to the present invention that is sufficient to produce a desired therapeutic outcome. "Administering" refers to the physical introduction of a composition comprising said therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art. The agents used in the present invention may be administered by any means that achieve their intended purpose. For example, administration may be, for example, by injection, intravenous, intramuscular, intraperitoneal, intratumoral, subcutaneous, or other parenteral routes of administration. In addition to the pharmacologically active compound, the pharmaceutical preparation of the agent preferably contains a suitable pharma- ceutically acceptable carrier, including excipients and adjuvants that facilitate processing of the active agent into a pharma- ceutically usable preparation. The selected dose should be sufficient to reduce or inhibit malignant tumor growth and / or inhibit metastasis formation.

[0024] The method according to the present invention for deciding to treat a cancer patient before starting anti-CLEVER-1 therapy, and also the method for treating cancer, are applicable to all forms of cancer. Thus, any malignant tumor or metastasis can be treated. In one embodiment according to the present invention, the anti-CLEVER-1 therapy is used to treat an advanced solid tumor. According to one embodiment of the present invention, the anti-CLEVER-1 therapy is used to treat a cancer selected from at least melanoma, gastric cancer, and cholangiocarcinoma.

[0025] Experimental part Human studies of CLEVER-1 inhibition for the treatment of cancer The anti-CLEVER-1 antibody FP-1305, a CLEVER-1 inhibitor, is currently being tested for safety and preliminary efficacy in a Phase I / II study in patients with advanced solid tumors (clinicaltrials.gov NCT03733990:A Study to Evaluate Safety,Tolerability and Preliminary Efficacy of FP-1305 in Cancer Patients (MATINS)).

[0026] The anti-CLEVER-1 antibody FP-1305 is a humanized monoclonal CLEVER-1 antibody previously presented in Patent Publication No. WO2017 / 182705. More precisely, FP-1305 (DSM ACC3361) is a humanized monoclonal immunoglobulin G4 κ antibody bexmarilimab (proposed International Nonproprietary Name (INN) disclosed in WHO Drug Information, Vol. 33, No. 4 (2019) and recommended INN in WHO Drug Information, Vol. 34, No. 3 (2020), pp. 699-700).

[0027] In this study, a first (pre-dose) serum sample is taken from the patient prior to initiating administration of FP-1305 (bexmarilimab). IFNg, TNF-α, IL-6, and IL-8 levels, as well as C-reactive protein (CRP), are measured from the standard serum sample using conventional measurement methods known in the art.

[0028] In this study, patients will receive anti-CLEVER-1 antibody at a dose of 1 mg / kg administered every 3 weeks for an indefinite period until disease progression.

[0029] result In the MATINS trial, approximately 30% of patients with advanced melanoma, gastric cancer, and cholangiocarcinoma responded favorably to the anti-CLEVER-1 IgG4 antibody bexmarilimab (FP-1305).

[0030] As shown in Figures 1-3, inflammatory marker data extracted from these expansion cohorts of the First-in-Human Bexumalilimab Trial (MATINS) show that subjects who showed clinical benefit from bexumalilimab in Kaplan-Meier survival analyses had significantly lower baseline serum IFNg and TNF-α levels, indicating that bexumalilimab may be particularly effective in so-called highly immunosuppressed, non-inflammatory "cold" tumors.

[0031] More specifically, of 30 patients, all of whom were heavily pretreated and refractory to checkpoint inhibitors, there were 9 who experienced clinical benefit (partial response or stable disease) and 21 who did not experience clinical benefit after treatment with bexmarilimab. At baseline, the 9 patients who experienced clinical benefit had mean serum interferon gamma (IFNg) levels of 5.11 pg / ml (SD, + / - 4.99 pg / ml) compared to 13.07 pg / ml (SD, + / - 13.26) in patients who did not experience clinical benefit after treatment with bexmarilimab (Figure 2). Similarly, serum tumor necrosis factor alpha (TNF-α) levels at baseline in patients who experienced clinical benefit were 0.96 pg / ml (SD, + / - 0.74 pg / ml) compared to 2.37 pg / ml (SD, + / - 1.43 pg / ml) in patients who did not experience clinical benefit after treatment with bexmarilimab (Figure 3). Based on receiver operating characteristic (ROC) curve analysis, 83% of patients with low levels of IFNg and TNF-α are expected to experience clinical benefit when treated with bexmarilimab (Figure 4). When classical pro-inflammatory cytokines such as interleukin 6 (IL-6) and / or interleukin 8 (IL-8) are added to the ROC analysis, the likelihood of predicting response to bexmarilimab increases to 91% (Figure 5). Also, the standard inflammatory lab C-reactive protein (CRP) has a good ability to reflect non-inflammatory cancer types that respond to bexmarilimab (Figure 6).

[0032] Therefore, based on the above analysis of patients who showed clinical benefit from the anti-CLEVER-1 antibody bexmarilimab in Kaplan-Meier survival analysis, it can be concluded that the decision to start anti-CLEVER-1 antibody therapy can be made using the inflammatory marker. The response to anti-CLEVER-1 antibody therapy will be better if the level of the inflammatory marker is at a normal average level or below the baseline value before starting therapy. If the level of the inflammatory marker is abnormally high compared to the baseline value, it may lead to non-responsiveness to anti-CLEVER-1 antibody therapy, and other treatment options are more likely to be better.

[0033] TIFF2024545101000002.tif224147 TIFF2024545101000003.tif77147

Claims

1. 1. A method for selecting a patient for anti-CLEVER-1 therapy prior to initiating anti-CLEVER-1 therapy, said CLEVER-1 therapy comprising administration of an agent capable of binding to CLEVER-1 in a patient, said method comprising: - providing a blood sample obtained from said patient at a first time point prior to initiating anti-CLEVER-1 therapy; - measuring from said sample the level of one or more inflammatory markers selected from the group consisting of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP); - comparing the measured level of the inflammatory marker with a reference value of the inflammatory marker; wherein the measured level of the inflammatory marker being substantially within the reference value for the inflammatory marker or lower than an average reference value for the inflammatory marker is an indication for selecting the patient and initiating the anti-CLEVER-1 therapy.

2. The method of claim 1 , wherein the patient is a cancer patient.

3. The method according to claim 1 or 2, characterized in that the anti-CLEVER-1 agent comprises an anti-CLEVER-1 antibody, preferably the anti-CLEVER-1 antibody bexmarilimab, as disclosed in WHO Drug Information, Vol. 33, No. 4, pages 814-815 (2019).

4. The method of any one of claims 1 to 3, characterized in that the anti-CLEVER-1 agent comprises the anti-CLEVER-1 antibody bexmarilimab (FP-1305) deposited under accession number DSM ACC3361.

5. The method according to any one of claims 1 to 4, characterized in that said method comprises measuring at least the levels of interferon gamma (IFNg) and tumor necrosis factor alpha (TNF-α).

6. 6. The method according to any one of claims 1 to 5, characterized in that the method comprises measuring the levels of interferon gamma (IFNg), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and / or interleukin 8 (IL-8) in combination with measuring the level of C-reactive protein (CRP).

7. The method according to any one of claims 1 to 6, characterized in that the levels of the inflammatory markers are measured from serum and / or plasma.

8. The method according to any one of claims 1 to 7, characterized in that the anti-CLEVER-1 therapy is used to treat an advanced solid tumor.

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