Combination therapy for classic hodgkin's lymphoma

Abstract

To provide a pharmaceutical composition for use in the treatment of classic Hodgkin's lymphoma (cHL) in a subject in need thereof comprising a recombinant fusion protein.SOLUTION: The pharmaceutical composition is administered with an anti-PD-1 antibody, where the recombinant fusion protein comprises a mutanted SIRPα D1 domain and a functional IgG1 heavy chain constant region, where the mutated SIRPα D1 domain comprises a specific amino acid sequence.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to a pharmaceutical composition for use in treating classical Hodgkin's lymphoma (cHL) in a subject in need thereof, comprising a recombinant fusion protein administered in combination with an anti-PD-1 antibody, the recombinant fusion protein having a mutated SIRPαD1 domain and a functional IgG1 heavy chain constant region, wherein the mutated SIRPαD1 domain comprises the amino acid sequence of SEQ ID NO:2. [Background technology]

[0002] Lymphoma, one of the most common malignant tumors, affects the lymphatic system, which plays a key role in both immune function and the drainage of excess extracellular fluid. According to a 2018 report from the National Cancer Center of China, lymphoma was the 10th leading cause of death in 2015, with an incidence rate of approximately 6.89 cases per 100,000 population. Lymphomas can be classified as Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Classical Hodgkin's lymphoma (cHL) accounts for approximately 90% of HL cases, and the 5-year overall survival rate for patients with advanced-stage cHL is 56% to 89% (Guidelines for the Diagnosis and Treatment of Lymphoma (2018) by the National Health Commission of the People's Republic of China). Currently, chemotherapy regimens, including ABVD and AVD, achieve favorable efficacy in 75%–85% of cHL patients, with an overall response rate (ORR) exceeding 90% (Lai C. et al., (2019) Blood and Lymphatic Cancer: Targets and Therapy 9:63-71; Song Y. et al., (2020) Leukemia 34(2):533-542). However, some cHL patients do not respond to such chemotherapy or suffer from chemotherapy side effects. Approximately 10%–15% of early-stage cHL patients and 15%–30% of late-stage cHL patients develop relapsed or refractory (R / R) disease.

[0003] In recent years, the emergence of immunotherapies targeting PD-1 / PD-L1 signaling has shown promise for this treatment of patients with cHL. Anti-PD-1 / PD-L1 antibodies, such as nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab, have been approved as clinical treatments for relapsed / refractory cHL. In a phase II, open-label, single-arm, multicenter study (ClinicalTrials.gov identification number NCT03209973), tislelizumab demonstrated its efficacy and safety as a single agent in the treatment of relapsed / refractory cHL. Seventy patients with relapsed or refractory cHL who had failed to achieve a response or progressed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT were enrolled, of whom 60 were in stages IIb–IV. These patients received 200 mg of tislelizumab every 3 weeks until progressive disease or unacceptable adverse side effects occurred, resulting in an objective response rate (ORR) of 87.1% and a complete remission rate (CR) of 67.1% at a median follow-up of 33.8 months. The 3-year progression-free survival (PFS) and overall survival rates were 40.8% and 84.8%, respectively (Song Y. et al., (2022) Clin Cancer Res. 28(6):1147-1156). Other anti-PD-1 antibodies, including pembrolizumab, nivolumab, and sintilimab, have achieved CR rates of approximately 21% to 34% in the treatment of relapsed / relapsed cHL, meaning that most patients treated with such monotherapy did not meet remission criteria and required further treatment (Chen R. et al., (2019) Blood 134(14):1144-1153). Combining anti-PD-1 and chemotherapy may benefit these patients. For example, the combination of nivolumab and AVD achieved complete remission in 85% of patients with initially poor-prognosis cHL. The complete remission rate was approximately 67% with non-first-line therapy using nivolumab and brentuximab vedotin, while camrelizumab in combination with decitabine achieved a CR of 71%.

[0004] Magrolimab, a humanized IgG4 anti-CD47 antibody, is currently undergoing clinical trials in combination with pembrolizumab to treat classical Hodgkin lymphoma. When bound to the CD47 molecule on tumor cells, magrolimab inhibits CD47 from binding to signal regulatory protein alpha (SIRPα) on immune cells, potentially enhancing the ability of macrophages and other phagocytes to identify and destroy malignant cells. However, the FDA previously placed a partial clinical hold on one magrolimab clinical trial due to suspected unexpected serious adverse reactions.

[0005] In addition to tumor cells, normal human red blood cells also express the CD47 protein, so safety issues have hindered nearly all conventional anti-CD47 antibodies. Binding of anti-CD47 antibodies to red blood cells can cause severe hemolysis and anemia. To alleviate on-target anemia, a priming dose of anti-CD47 antibodies can be administered to selectively eliminate senescent red blood cells while sparing younger red blood cells that lack phagocytic signals.

[0006] There is a continuing and urgent need for more effective therapies with fewer adverse side effects for treating patients with classical Hodgkin's lymphoma.

[0007] Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. Summary of the Invention

[0008] The present inventors have designed a combination therapy for classical Hodgkin lymphoma (cHL) using a recombinant fusion protein and an anti-PD-1 antibody. The recombinant fusion protein contains i) a mutant SIRPαD1 as a ligand trap for CD47 neutralization, and ii) a functional IgG1 heavy chain constant region, including an Fc region, that can induce recombinant fusion protein-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity against cells bound by the mutant SIRPαD1. The mutant SIRPαD1 contains a single point mutation from asparagine to alanine at position 80 of SIRPαD1 and exhibits higher binding ability to CD47 on Jurkat leukemia cells and minimal binding to erythrocytes compared to wild-type SIRPαD1.

[0009] Clinical trial data collected through February 2024 indicate that the combination therapy was well tolerated, achieving a 75% objective response rate (ORR) and a 100% disease control rate (DCR) in enrolled cHL patients. The combination therapy is particularly effective in treating patients with relapsed or refractory cHL (R / R cHL) who have failed prior anti-PD-1 monotherapy. Furthermore, the combination therapy did not require a priming dose and produced minimal hemolytic anemia.

[0010] Thus, in a first aspect, the present disclosure provides i) a recombinant fusion protein which may comprise a mutant SIRPαD1 and a functional IgG1 heavy chain constant region, and ii) a pharmaceutical composition which may comprise an anti-PD-1 antibody.

[0011] The mutant SIRPαD1 may be human SIRPαD1 comprising a mutation from asparagine (Asn, N) to alanine (Ala, A) at a site corresponding to position 80 of SEQ ID NO: 2. The mutant SIRPαD1 may comprise the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the mutant SIRPαD1 may consist of the amino acid sequence of SEQ ID NO: 2.

[0012] The functional IgG1 heavy chain constant region can be an IgG1 heavy chain constant region or a fragment thereof (e.g., Fc region) capable of binding to an Fc receptor to induce recombinant fusion protein-dependent cell-mediated cytotoxicity, or capable of binding to a complement system protein to induce complement-dependent cytotoxicity. The functional IgG1 heavy chain constant region can be a human IgG1 heavy chain constant region or its Fc region. The functional IgG1 heavy chain constant region can be, for example, the Fc region of a human IgG1 heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 3. In a specific embodiment, the functional IgG1 heavy chain constant region can be composed of the amino acid sequence of SEQ ID NO: 3.

[0013] The recombinant fusion protein may comprise, from N- to C-terminus, a mutant SIRPαD1 and a functional IgG1 heavy chain constant region. The recombinant fusion protein may have, and in certain embodiments, consist of, the amino acid sequence of SEQ ID NO:1.

[0014] The anti-PD-1 antibody can be tislelizumab, nivolumab, pembrolizumab, sintilimab, or camrelizumab. In certain embodiments, the anti-PD-1 antibody can be tislelizumab.

[0015] The pharmaceutical compositions of the present disclosure may further comprise a pharmaceutically acceptable excipient.

[0016] In a second aspect, the present disclosure may provide a pharmaceutical composition that may include the recombinant fusion protein for use in treating classical Hodgkin lymphoma (cHL) in a subject in need thereof, wherein the pharmaceutical composition is administered in combination with an anti-PD-1 antibody.

[0017] The recombinant fusion protein may comprise a mutant SIRPαD1 and a functional IgG1 heavy chain constant region. The mutant SIRPαD1 may be human SIRPαD1 comprising an asparagine (Asn, N) to alanine (Ala, A) mutation at the site corresponding to position 80 of SEQ ID NO: 2. The mutant SIRPαD1 may comprise the amino acid sequence of SEQ ID NO: 2. In a specific embodiment, the mutant SIRPαD1 may consist of the amino acid sequence of SEQ ID NO: 2. The functional IgG1 heavy chain constant region may be an IgG1 heavy chain constant region or a fragment thereof (e.g., Fc region) capable of binding to an Fc receptor to induce recombinant fusion protein-dependent cell-mediated cytotoxicity or a complement system protein to induce complement-dependent cytotoxicity. The functional IgG1 heavy chain constant region may be a human IgG1 heavy chain constant region or its Fc region. The functional IgG1 heavy chain constant region may be, for example, the Fc region of a human IgG1 heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the functional IgG1 heavy chain constant region may consist of the amino acid sequence of SEQ ID NO: 3. The recombinant fusion protein may comprise, from N- to C-terminus, a mutant SIRPαD1 and a functional IgG1 heavy chain constant region. The recombinant fusion protein may comprise, and in certain embodiments consist of, the amino acid sequence of SEQ ID NO: 1.

[0018] The anti-PD-1 antibody can be tislelizumab, nivolumab, pembrolizumab, sintilimab, or camrelizumab. In certain embodiments, the anti-PD-1 antibody can be tislelizumab.

[0019] The treatment may involve intravenously administering to a subject i) a recombinant fusion protein at a dose of about 2.0 mg / kg body weight once a week, and ii) an anti-PD-1 antibody at a dose of about 200 mg once every three weeks.

[0020] If the recombinant fusion protein and anti-PD-1 antibody are administered on the same day, the recombinant fusion protein can be administered at least 30 minutes after administration of the anti-PD-1 antibody is completed.

[0021] The recombinant fusion proteins of the present disclosure can be administered by intravenous infusion over 180±15 minutes for the first infusion, 120±15 minutes for the second infusion, and 60±15 minutes for subsequent infusions.

[0022] The anti-PD-1 antibody may be administered by intravenous infusion over 60 minutes or longer for the first infusion and, if well tolerated, over 30 minutes or longer for subsequent infusions.

[0023] In certain embodiments, the treatment may include the following steps: (a) intravenously administering to a subject about 200 mg of an anti-PD-1 antibody in the form of a composition comprising a pharmaceutically acceptable excipient and the anti-PD-1 antibody; (b) intravenously administering to the subject about 2.0 mg / kg body weight of the recombinant fusion protein in the form of a composition comprising a pharmaceutically acceptable excipient and the recombinant fusion protein; and (c) after steps (a) and (b), repeating step (a) once every three weeks and repeating step (b) once a week.

[0024] Step (b) can be performed at least 30 minutes, for example about 30 minutes, after completing the administration of step (a).

[0025] Step (b) may be performed at least 30 minutes after completing step (a).

[0026] In step (c), the recombinant fusion protein may be administered about 30 minutes after completing the repeated administration of step (a) on the day the subject also repeats step (a).

[0027] The treatment may not include administration of a priming dose of a recombinant fusion protein or a dose ramp-up dose of a recombinant fusion protein to alleviate the targeted anemia.

[0028] The treatment may produce an objective response rate of greater than 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% after 24 weeks or longer of treatment. The objective response rate may be defined as the sum of the complete response (CR) rate and the partial response (PR) rate.

[0029] The treatment may result in complete response rates of greater than 20%, 25%, 30%, 35%, 40% or 45% after 24 weeks or longer of treatment.

[0030] The treatment may result in a disease control rate of greater than 85%, 90%, or 95% after 24 weeks or longer of treatment. Disease control rate may be defined as the sum of the complete response (CR), partial response (PR), and stable disease (SD) rates.

[0031] Treatment-related hemolytic anemia may occur in no more than 5% or 10% of treated subjects.

[0032] No more than 15% or 20% of treated subjects are likely to discontinue treatment due to treatment-related adverse effects.

[0033] The subject may be human. The subject may have relapsed or refractory cHL. The subject may have experienced failure of a previous anti-PD-1 therapy. In certain embodiments, the subject may have experienced failure of a previous tislelizumab therapy. In certain embodiments, the subject may be resistant to tislelizumab therapy. In certain embodiments, the subject may have experienced failure of a previous other non-tislelizumab PD-1 therapy. In certain embodiments, the subject may be resistant to other non-tislelizumab PD-1 antibodies.

[0034] Other features and advantages of the present disclosure will become apparent from the following detailed description and examples, which should not be construed as limiting. The contents of all references, GenBank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0035] Accordingly, it is the object of the present invention not to encompass within the present invention any known products, processes for making a product, or methods for using a product, and therefore, Applicant reserves the right to disclose and discloses herein any known products, processes, or methods. Furthermore, it is noted that the present invention does not intend to encompass within its scope any products, processes, or methods for making a product or using a product that do not meet the description and enablement requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 EPC), and therefore, Applicant reserves the right to disclose and disclose herein any previously described products, processes for making a product, or methods for using a product. Compliance with Article 53(c) of the EPC and Rules 28(b) and (c) of the EPC may be advantageous in the practice of the present invention. All rights are expressly reserved to explicitly disclaim any embodiments that are the subject of any licensed patent of Applicant in this or any other line, or in any prior application of any third party. Nothing herein should be construed as a promise.

[0036] It is noted that in this disclosure, particularly in the claims and / or paragraphs, terms such as "comprises," "comprised," and "comprising," etc., may have the meaning ascribed to them in U.S. patent law; e.g., they may mean "includes," "included," and "including," etc.; and terms such as "consisting essentially of" and "consists essentially of" have the meaning ascribed to them in U.S. patent law, e.g., they allow for elements not expressly recited, but exclude elements found in the prior art or that affect the basic or novel characteristics of the invention. [Brief explanation of the drawings]

[0037] The following detailed description is given by way of example, but is not intended to limit the invention to only the particular embodiments described, and may be best understood in conjunction with the accompanying drawings, in which:

[0038] [Figure 1] Individual responses and duration of response in cHL patients are shown.

[0039] [Figure 2] The maximum percent change in tumor size from baseline in cHL patients is shown. DETAILED DESCRIPTION OF THE INVENTION

[0040] Cancer cells may have developed several methods to escape host immune surveillance. For example, cancer cells can express high levels of CD47 protein on their surface, which can bind to signal-regulatory protein alpha (SIRPα) on the surface of macrophages, thereby inducing an inhibitory signal that inhibits phagocytosis of cancer cells by macrophages. Tumor cells can also constitutively express PD-L1 molecules, which can bind to PD-1 molecules on immune cells, causing T cell dysfunction and immune unresponsiveness, and IL-10 secretion.

[0041] Signal-regulatory receptor proteins (SIRPs) are transmembrane glycoproteins that include three family members: SIRPα (CD172a), SIRPβ (CD172b), and SIRPγ (CD172g). All three proteins have similar extracellular regions but distinct intracellular domains. The extracellular regions contain three immunoglobulin-like domains, one Ig V-set, and two Ig C-set domains. The intracellular domain of SIRPα contains two inhibitory signaling regions that can inhibit signal transduction and corresponding cellular functions. SIRPβ and SIRPγ have very short intracellular regions without any signaling domains. However, SIRPβ can function through adaptor proteins, such as DAP12, for signal transduction. SIRPs are primarily expressed on macrophages (Mφ), dendritic cells (DCs), and neurons.

[0042] CD47 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is expressed on the surface of all cell types, including red blood cells. Ligands for CD47 include integrins, thrombospondin-1, and SIRPs. CD47 can inhibit phagocytosis by macrophages by interacting with SIRPα to signal "don't eat me," thereby protecting cells such as blood cells from attack by macrophages.

[0043] Studies have shown that many tumor or cancer cells overexpress CD47, which prevents macrophages from phagocytosing cancer cells. CD47-overexpressing cancer cells include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, breast cancer, and pancreatic cancer cells. It has been reported that injection of a CD-47-specific antibody that inhibits CD47 binding to SIRPα significantly inhibits tumor growth in tumor-bearing mice. When the same antibody was injected into mice bearing human leukemia cells, the tumor or cancer cells were completely eliminated (Theocharides, APA et al. (2012) J. Exp. Med. 209(10):1883-1899).

[0044] Conventional anti-CD47 antibodies bind strongly to CD47 on normal human erythrocytes, thereby creating an "antigen sink" effect, exhibiting relatively low efficacy against tumor cells and requiring much higher doses (10-30 mg / kg) for efficacy. In addition, to avoid hemolysis and anemia caused by CD47 binding on erythrocytes, conventional anti-CD47 antibodies employ an IgG4 or IgG2 design in their Fc region and may require a priming or "ramp-up" dose, as is the case for magrolimab. As a result, anti-CD47 antibodies exhibit high hematologic toxicity and minimal single-agent efficacy, requiring combination therapy (with another tumoricidal agent) to achieve antitumor efficacy in vivo (Joseph Maakaron et al., (2022) Blood 140(Supplement 1):3728-3730; David Andrew Sallman et al., (2023) Journal of Clinical Oncology 40(no.16_suppl):7017-7017; Naval Guastad Daver. Journal of Clinical Oncology 40(no.16_suppl):7020-7020).

[0045] In contrast, the present mutant SIRPαD1-Fc molecule, designated IMM01 (timdarpacept), utilizes SIRPα extracellular domain 1 as a ligand trap for CD47 neutralization, which is more tumor-specific than anti-CD47 antibodies and exhibits minimal binding to erythrocytes in vivo (data not shown). The SIRPαD1 in IMM01 contains a single point mutation from asparagine to alanine at position 80 of the SIRPα sequence. As shown in Figure 7B of US10800821B2, HY03M, which has an identical sequence except for nine additional amino acids at the amino terminus compared to IMM01, binds to the CD47 protein on Jurkat leukemia cells with higher affinity than the wild-type SIRPαD1-Fc molecule. Due to its high tumor specificity, IMM01 also employs an IgG1 design in its Fc portion for significantly more effective antitumor efficacy as a single agent. Indeed, Figure 10B of US10800821B2 shows that HY03MM, an IgG1-deficient version of HY03M, has much lower antitumor efficacy than the IgG1-competent version of HY03M. Furthermore, IMM01 (timdarpacept) does not require a priming dose and produces minimal hemolytic anemia and minimal grade 3 and 4 treatment-related hemolysis (Example 4).

[0046] PD-1 is an immune checkpoint molecule that is primarily expressed on memory T cells and exerts an inhibitory effect on immune responses. PD-L1 and PD-L2 are PD-1 ligands. PD-L1 molecules are constitutively expressed on antigen-presenting cells, T cells, B cells, monocytes, and epithelial cells, and their levels are upregulated in many cells in the presence of proinflammatory cytokines (Keir ME et al., (2008) supra; Chen J et al., (2016) Ann Oncol. 27(3):409-416). Studies have shown that PD-L1 signaling can exert an inhibitory effect on T cells and also on B cell- and NK cell-mediated lysis in some ways, and that antibody-mediated PD-1 or PD-L1 blockade can result in durable tumor regression in cancer patients (Dong H et al., (1999) Nat Med. 5(12):1365-1369; Keir ME et al., (2008) supra; Chen J et al., (2016) supra; Terme M et al., (2011) Cancer Res. 71(16):5393-5399; Fanoni D et al., (2011) Immunol Lett. 134(2):157-160). However, not all patients respond, and patients may develop relapsed or refractory (R / R) disease.

[0047] Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignant tumor characterized by a tumor microenvironment (TME) composed of a small number of malignant Hodgkin and Reed-Sternberg (HRS) cells, surrounded by leukocytes consisting of T cells, B cells, mast cells, macrophages, plasma cells, eosinophils, and mesenchymal stromal cells. Studies have shown that cHL patients with high expression of CD47 on HRS cells have significantly inferior event-free survival and overall survival (OS) (Gholiha AR et al. (2022) Br J Haematol. 197(5):580-589).

[0048] This application provides a combination therapy for cHL patients using i) a recombinant fusion protein that binds CD47 and ii) an anti-PD-1 antibody. Such therapy is well tolerated and is particularly efficacious in treating patients with relapsed or refractory cHL (R / R cHL) who have failed previous anti-PD-1 monotherapy.

[0049] The recombinant fusion protein contains i) a mutant SIRPαD1 as a ligand trap for CD47 neutralization, and ii) a functional IgG1 heavy chain constant region, such as an Fc region, that can induce recombinant fusion protein-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity against cells bound by the mutant SIRPαD1. An example of a recombinant fusion protein is IMM01. Two copies of the recombinant fusion protein can dimerize to form an IgG1 antibody-like molecule via disulfide bonds between the functional IgG1 heavy chain constant regions. As an IgG1 antibody-like molecule, the recombinant fusion protein has the general structure of an IgG1 antibody, and the SIRPαD1 portion is the "paratope" or CD47-binding moiety.

[0050] The mutant SIRPαD1 may be human SIRPαD1 comprising an asparagine (Asn, N) to alanine (Ala, A) mutation at the site corresponding to position 80 of SEQ ID NO: 2. The mutant SIRPαD1 may comprise the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the mutant SIRPαD1 may consist of the amino acid sequence of SEQ ID NO: 2.

[0051] The term "functional IgG1 heavy chain constant region" refers to an IgG1 heavy chain constant region or a fragment thereof (e.g., Fc region) that can bind to an Fc receptor to induce recombinant fusion protein-dependent cell-mediated cytotoxicity, or that can bind to a complement system protein to induce complement-dependent cytotoxicity. A functional IgG1 heavy chain constant region must contain an Fc region to exert the above-mentioned cytotoxicity.

[0052] The Fc region, or fragment crystallizable region, is the tail region of an antibody and is the domain that determines the antibody's effector function, i.e., how it engages with specific cellular receptors or other defense proteins. The Fc region can interact with Fc receptors and / or proteins of the complement system to activate the immune system. For example, Fc receptors can bind to Fc-containing molecules (e.g., antibodies or recombinant fusion proteins of the present disclosure) attached to infected cells or invading pathogens, stimulating phagocytes or cytotoxic cells to destroy the microorganisms or infected cells. Fc receptors (FcRs) are found on the surface of certain immune effector cells, including B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, and mast cells.

[0053] The term "recombinant fusion protein-dependent cell-mediated cytotoxicity" as used herein refers to an immune mechanism through which effector cells bearing Fc receptors recognize and kill target cells coated with Fc-containing molecules (e.g., recombinant fusion proteins of the present disclosure, such as IMM01) that express antigens from tumors or pathogens on their surface.

[0054] "Complement-dependent cytotoxicity" is the mechanism by which an Fc-containing molecule (e.g., a recombinant fusion protein of the present disclosure, such as IMM01) mediates the lysis of specific target cells through activation of an organism's complement system. CDC is initiated when C1q, the initiating component of the classical complement pathway, fixes to the Fc portion of an Fc-containing molecule bound to a target cell.

[0055] In certain embodiments, the functional IgG1 heavy chain constant region may be, for example, the Fc region of a human IgG1 heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the functional IgG1 heavy chain constant region may be composed of the amino acid sequence of SEQ ID NO: 3.

[0056] The recombinant fusion protein may comprise, from N- to C-terminus, a mutant SIRPαD1 and a functional IgG1 heavy chain constant region. The recombinant fusion protein may comprise, and in certain embodiments, consist of, the amino acid sequence of SEQ ID NO:1.

[0057] The anti-PD-1 antibody can be any anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is tislelizumab.

[0058] The present disclosure may provide compositions, e.g., pharmaceutical compositions, comprising a recombinant fusion protein and an anti-PD-1 antibody. The recombinant fusion protein may be formulated with a pharmaceutically acceptable carrier. The anti-PD-1 antibody may be formulated with a pharmaceutically acceptable carrier.

[0059] A pharmaceutically acceptable carrier generally means a carrier that is safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers that are acceptable for veterinary use as well as human pharmaceutical use. The primary carrier used in pharmaceutical compositions can be either aqueous or non-aqueous in nature. For example, suitable carriers can be water for injection, saline, or artificial cerebrospinal fluid, optionally supplemented with other substances commonly used in injections. For example, the vehicle or carrier can be neutral buffered saline or saline mixed with serum albumin. Other exemplary pharmaceutical compositions include Tris buffer, which may further contain sorbitol or a suitable substitute thereof, or acetate buffer. In one embodiment of the present disclosure, compositions can be prepared for storage by mixing a selected recombinant fusion protein or anti-PD-1 antibody having the desired purity with optional formulating agents in the form of a lyophilized cake or aqueous solution. Furthermore, the recombinant fusion protein and / or anti-PD-1 antibody can be formulated as a lyophilizate using appropriate excipients, such as sucrose, and reconstituted with saline (i.e., 0.9% sodium chloride solution) prior to administration.

[0060] Pharmaceutical compositions may contain any number of excipients. Excipients that can be used include carriers, surfactants, thickeners or emulsifiers, binders, dispersing or suspending aids, solubilizers, colorants, flavoring agents, coating agents, disintegrants, lubricants, sweeteners, preservatives, isotonicity agents, and combinations thereof. The selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003).

[0061] Recombinant fusion proteins and anti-PD-1 antibodies can be formulated for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the recombinant fusion protein or anti-PD-1 antibody may be coated with a material to protect it from the action of acids and other natural conditions that may inactivate it. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. In particular, recombinant fusion proteins and anti-PD-1 antibodies can be administered intravenously, for example, by intravenous infusion.

[0062] The amount of recombinant fusion protein or anti-PD-1 antibody that may be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated, the particular mode of administration, the site of the lesion, etc., and will generally be an amount that produces a therapeutic effect.

[0063] In particular, the recombinant fusion proteins of the present disclosure may be provided in the form of a protein dispersion or lyophilized powder that can be dispersed in whatever is applicable, such as water for injection.

[0064] The anti-PD-1 antibodies of the present disclosure may be provided in the form of a protein dispersion or lyophilized powder that can be dispersed in whatever is applicable, for example, water for injection.

[0065] Dosage regimens can be adjusted to provide the optimum desired response (e.g., therapeutic response). For example, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary doses for the subject to be treated; each unit contains a predetermined quantity of an active molecule calculated to produce the desired therapeutic effect in association with the necessary pharmaceutical carrier. Alternatively, the recombinant fusion protein or anti-PD-1 antibody can be administered as a sustained-release formulation, in which case less frequent administration is required.

[0066] In another aspect, the present application provides a method for treating classical Hodgkin's lymphoma (cHL) in a subject in need thereof.

[0067] For the Phase Ib and Phase II clinical studies, inclusion criteria for patient cohorts include: 1. Subjects must be able to voluntarily sign an informed consent form, be able to communicate satisfactorily with the investigator, and be willing to comply with the study regulations; 2. Male or female, aged 18 years or older; 3. Life expectancy is 12 weeks or more; 4. Clinical diagnosis: (1) Phase 1b: Subjects with advanced solid tumors diagnosed by histology or cytology who have failed previous standard treatments (including anti-PD-1 / PD-L1 monotherapy or combination therapy) or who are unable to receive such treatment due to the lack of standard treatments for their specific tumor; (2) Phase 2: Subjects with histologically confirmed cHL who have experienced failure of systemic second-line therapy or autologous stem cell transplant (ASCT), including subjects who (a) responded to anti-PD-1 therapy but relapsed, or (b) did not respond to prior anti-PD-1 therapy. 5. Subjects must have at least one measurable tumor lesion according to RECIST v1.1 or the 2014 Lugano Recommendations for Lymphoma (National Cancer Institute) and have received local treatment such as radiation therapy, but one tumor lesion that has progressed or worsened according to RECIST v1.1 may be considered a measurable tumor lesion; 6.ECOG PS 0 or 1; 7. For patients with hepatocellular carcinoma, the Child-Pugh score is A or B and there is no hepatic encephalopathy; 8. Adequate organ function, including bone marrow, liver, kidney, heart, and coagulation; 9. Adverse events associated with previous antitumor therapy have returned to Grade 1 or less according to NCI CTCAE V5.0; 10. When signing the informed consent form, women and men of childbearing potential must agree to practice effective contraception throughout the study and for 6 months after the final dose.

[0068] Exclusion criteria included: 1.a) Subjects who have received previous systemic anti-tumor therapy and are still within 4 weeks or 5 half-lives (T1 / 2) of receiving the previous therapy before the first dose of the current study; b) Subjects who have received hormonal therapy, small molecule targeted therapy, oral fluorouracil-based drugs, and / or endocrine therapy within 2 weeks before the first dose of the current study; c) Subjects who have received local palliative care within 2 weeks before the first dose of the current study; d) Subjects who have received non-specific immunomodulatory therapy excluding IL-11 within 2 weeks before the first dose of the current study; e) Subjects who have taken traditional Chinese medicine or original Chinese herbal medicine within 1 week before the first dose of the current study; 2. Subjects who have previously received treatment with a monoclonal anti-CD47 antibody or a SIRPα-containing fusion protein; 3. a) Subjects with healed CNS metastases within 2 weeks prior to the first dose of the current study, with no new lesions, and who, if applicable, discontinued corticosteroids at least 3 days prior to the first dose of the current study; b) Subjects with symptomatic or progressive central nervous system (CNS) metastases who have not received prior treatment, excluding those with small CNS metastatic lesions (≤1.5 cm in length). 4. Subjects with uncontrolled hypertension, pulmonary hypertension, or unstable angina; myocardial infarction, chronic heart failure (NYHA G3 / 4) within 6 months prior to the first dose of the current study; valvular disease; severe arrhythmia; or a history of CVA or TIA within 6 months prior to the first dose of the current study; 5. Subjects with a history of arterial thrombosis, deep vein thrombosis, or pulmonary embolism within 3 months prior to the first dose of the current study; 6. Subjects with a history of moderate or severe dyspnea; currently requiring oxygen therapy; or with interstitial lung disease (ILD) or severe pneumonia, severe chronic obstructive pulmonary disease, or severe pulmonary dysfunction; 7. (a) Subjects who have been cured of cervical intraepithelial neoplasia or skin cancer (non-melanoma), b) Subjects who have been cured of a second primary tumor that has not recurred within 5 years, c) Subjects who have had another malignancy within 5 years prior to the first dose of the current study, excluding those with a second primary tumor who may benefit from the current study; 8. Subjects with diseases that may cause gastrointestinal bleeding or perforation; 9. Subjects with uncontrolled pleural effusion, ascites, or pericardial effusion; 10. Subjects with active hepatitis B (HBsAg positive and HBV-DNA level above a predetermined lower limit) or hepatitis C (anti-HCV positive and HCV RNA level above a predetermined lower limit); 11. Subjects with a history of immunodeficiency, including HIV infection or organ transplant; 12. Subjects with a history of autoimmune disease who still require immunosuppressive therapy or systemic hormone therapy, excluding those with hypothyroidism that can be controlled with hormone replacement alone, skin diseases that do not require systemic treatment, or controllable celiac disease; 13. Subjects who had an uncontrolled severe active infection within 4 weeks prior to the first dose of the current study; 14. Subjects with allergies (greater than Grade 3 by CTCAE 5.0) to study drugs, chimeric or humanized antibodies, or recombinant fusion proteins; 15. Subject has received a cancer treatment vaccine within 4 weeks prior to the first dose of the current study, or is planning to receive such a vaccine; 16. Subjects who have undergone major surgery within 4 weeks prior to the first dose of the current study, or minor surgical procedure within 2 weeks prior to the first dose of the current study, or who are scheduled to undergo major surgery within 1 week after taking study drug; 17. Subjects with a history of neurological or psychiatric disorders that affect compliance, such as epilepsy and dementia; 18. Subjects with a history of alcoholism or drug addiction within the past year; 19. Subjects who are pregnant or nursing an infant, or who are not willing to practice effective contraception throughout the study and for 6 months after the final dose of the current study; 20. Subjects who experienced adverse events associated with immunotherapy that led to permanent discontinuation; 21. Subject has any other condition that makes them unsuitable for participation in the current clinical trial in the opinion of the investigator.

[0069] Subjects must be screened within 28 days of signing the informed consent form (ICF). Eligible subjects will be treated with IMM01 in combination with anti-PD-1.

[0070] During treatment studies, tumor assessments must be performed every 6 weeks ± 7 days after the first dose of study drug, and tumor imaging may be arranged for subjects with suspected disease progression or new tumor lesions, or for subjects who discontinue treatment for any reason. Subjects who terminate the study must undergo tumor assessments every 12 weeks until disease progression, initiation of new anticancer treatment, or death. Phase I and II trials must and shall be terminated upon the last subject's withdrawal of consent, termination of treatment or withdrawal from the study, loss to follow-up or death, 48 weeks of treatment, or early termination of the study, whichever occurs first.

[0071] Subjects who discontinue treatment for any reason are required to complete a safety follow-up visit (28 ± 7 days after the last dose of study drug). Following completion of the safety follow-up period, these subjects will be followed for vital status. Subjects without disease progression or new anti-cancer treatment will continue to undergo tumor assessments (tumor imaging and evaluation) every 12 weeks ± 7 days until study end, initiation of new anti-cancer treatment, death, loss to follow-up, or 12 months after the last dose of study drug, whichever occurs first. Follow-up will end if new anti-cancer treatment is initiated. Follow-up visits will be discontinued for subjects who initiate new treatment. Subjects with disease progression may discontinue follow-up visits. If, in the investigator's judgment, the subject can still benefit from study drug treatment, treatment may be continued after consultation with the sponsor, but the subject must re-consent. The Sponsor also reserves the right to terminate a subject's access to the investigational drug if any of the following occurs (including, but not limited to): i) the Sponsor terminates the study; or ii) the subject has other reasonable treatment options.

[0072] Pretreatment before IMM01 infusion is recommended in Table 1 below. Table 1. Premedication for infusion-related reactions [Table 1]

[0073] The clinical trial design for the treatment of the present disclosure is as follows.

[0074] A traditional 3+3 design will be used for dose escalation of the IMM01 + anti-PD-1 combination in phase 1 clinical trials and to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D).

[0075] According to the Phase I clinical trial design, the IMM01 protein will be administered by intravenous infusion at a dose of 1.0 mg / kg, 1.5 mg / kg, or 2.0 mg / kg once weekly for a 3-week treatment cycle, and the anti-PD-1 antibody will be administered by intravenous infusion at a fixed dose of 200 mg once every 3 weeks for a 3-week treatment cycle. If IMM01 and anti-PD-1 are administered on the same day, the IMM01 infusion must be scheduled at least 30 minutes after the completion of anti-PD-1 administration. Subjects must cease treatment if they experience disease progression / death, intolerable toxicity, consent withdrawal, loss to follow-up, 48 weeks of treatment, or treatment discontinuation that is in the patient's best interest in the investigator's opinion, whichever occurs first.

[0076] The primary objectives of the Phase 1 study are i) to evaluate dose-limiting toxicities (DLTs) of IMM01 in combination with anti-PD-1 in subjects with advanced solid tumors, and ii) to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of IMM01 in combination with anti-PD-1 in subjects with advanced solid tumors, including type, incidence, and severity of adverse events (AEs), physical examination, laboratory tests, and changes in safety data (e.g., changes in physical examination results, laboratory tests, vital signs, ECG, ECHO per CTCAE V5.0 criteria).

[0077] Secondary objectives are: i) to evaluate the pharmacokinetic (PK) characteristics of IMM01 in combination with anti-PD-1 in subjects with advanced solid tumors, ii) to evaluate the immunogenicity of IMM01 in combination with anti-PD-1 in subjects with advanced solid tumors, and iii) to evaluate the preliminary anti-tumor activity of IMM01 in combination with anti-PD-1 in subjects with advanced solid tumors. Tumor assessments are required according to RECIST v1.1 and iRECIST, and parameters include objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), disease control rate (DCR), and time to response (TTR).

[0078] Exploratory objectives are: i) to explore the relationship between drug exposure and (where data permits) efficacy and safety of IMM01 in combination with anti-PD-1; ii) to explore correlations between predictive biomarkers and therapeutic endpoints. Exploratory endpoints include exposure-response (ER) (relationship between exposure and efficacy and safety of IMM01 in combination with anti-PD-1); biomarkers (relationship between PD-L1 expression and / or CD47 expression and response).

[0079] The MTD is defined as the highest dose at which dose-limiting toxicity (DLT) is observed in 1 / 6 or fewer subjects. To determine a dose level as the MTD, there must be at least 6 subjects with evaluable DLT data. Once the MTD is determined, the MTD is usually used as the RP2D, or a dose level below the MTD can be selected as the RP2D.

[0080] The RP2D was initially determined based on safety, PK, efficacy, and other data collected in the current dose-escalation study, combined with safety, tolerability, and PK / PD data from a dose-escalation study of IMM01 monotherapy for treating lymphoma (this is unpublished work), and was ultimately determined by a scientist review committee (SRC). The RP2D was also approved by the Center for Drug Evaluation and Research for a Phase II trial in the treatment of cHL.

[0081] The Phase II clinical study enrolled past and present patients with histologically diagnosed cHL who had failed systemic second-line therapy or autologous stem cell transplantation (ASCT). In the Phase II study, the IMM01 protein was administered intravenously at a dose of 2.0 mg / kg once weekly for a 3-week treatment cycle, and the anti-PD-1 antibody was administered intravenously at a fixed dose of 200 mg once every 3 weeks for a 3-week treatment cycle. If IMM01 and anti-PD-1 were administered on the same day, the IMM01 infusion should be scheduled at least 30 minutes after the completion of anti-PD-1 administration.

[0082] The primary objective of this Phase II study is to evaluate the preliminary antitumor activity of IMM01 in combination with anti-PD-1 in subjects with lymphoma. Primary endpoints include ORR by RECIST v1.1 or Luagano 2014.

[0083] Secondary objectives are to: i) evaluate the safety and tolerability of IMM01 in combination with anti-PD-1 in subjects with lymphoma, ii) evaluate the immunogenicity of IMM01 in combination with anti-PD-1 in subjects with lymphoma, and iii) evaluate the preliminary anti-tumor activity of IMM01 in combination with anti-PD-1 in subjects with lymphoma.Secondary endpoints include: i) type, incidence, and severity of adverse events (AEs), changes in physical examination, laboratory tests, and safety data (e.g., changes in physical examination results, laboratory tests, vital signs, ECG, and ECHO according to CTCAE V5.0 criteria), ii) positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAb), and iii) ORR by iRECIST; DoR by RECIST v1.1, iRECIST, or Lugano 2014, PFS, DCR, and TTR.

[0084] Exploratory objectives are: i) to explore the population pharmacokinetic (Pop-PK) characteristics of IMM01 in lymphoma (if data permit), ii) to explore correlations between IMM01 exposure and efficacy and safety (if data permit), and iii) to explore correlations between predictive biomarkers and therapeutic endpoints. Exploratory endpoints include Pop-PK (PK pharmacokinetics of IMM01 in lymphoma), ER (relationship between IMM01 exposure and efficacy and safety endpoints), and biomarkers (relationship between PD-L1 expression and / or CD47 expression and response).

[0085] Objective response rate (ORR) is a measure of how a particular treatment affects tumor burden in patients with a history of the tumor and is defined as the proportion of patients who respond either partially or completely to therapy.

[0086] Disease control rate (DCR) describes the proportion of patients with advanced cancer who experience a complete response, partial response, or stable disease following therapeutic intervention.

[0087] A complete response or complete remission (CR) is usually defined as the absence of detectable evidence of tumor. A partial response or partial remission (PR) indicates that further treatment will probably be needed to attempt a cure. In some slow-growing tumors (including low-grade lymphomas), further treatment may not be immediately necessary until the disease begins to increase in size again. Stable disease (SD) is usually used to describe a tumor that is neither growing nor shrinking. Progressive disease (PD) is a term that describes disease that progresses or gets worse.

[0088] Palliative and supportive treatment for symptoms associated with progressive tumors is permitted during the study, and medications for adverse reactions are also permitted. Medications that may induce or worsen clinical study symptoms are not permitted, and if such medications cannot be avoided, increased symptom monitoring is required.

[0089] Palliative local radiation therapy (within limited limits) for pain relief is permitted, and bisphosphonates or denosumab are permitted if bone metastases have already developed prior to enrollment. Subjects may use topical, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids. Physiological replacement doses of systemic corticosteroids (i.e., prednisone ≤ 10 mg / day) are permitted. Short-term corticosteroid use is permitted for prophylaxis (e.g., contrast allergy), for non-autoimmune disorders (e.g., delayed hypersensitivity reactions due to contact allergens), or for management of adverse reactions caused by the investigational drug.

[0090] Oral contraceptives, hormone replacement therapy, prophylactic or therapeutic anticoagulants, and other approved therapies may be continued.

[0091] The following treatments other than the investigational drug are prohibited during the study: 1. Any concomitant anti-tumor treatment (chemotherapy, immunotherapy, biologics, extensive radiation therapy, hormonal therapy, targeted therapy, surgery, interventional therapy and device therapy), investigational therapy, or approved therapy is not permitted; 2. Immunosuppressants are not permitted unless such agents are used for the treatment of immune-related adverse events; 3. Systemic corticosteroids with immunosuppressive effects are not permitted except for temporary hormone replacement therapy for infusion reactions, immune-related adverse reactions, or adrenal insufficiency (in such cases, the systemic corticosteroid dose for infusion reactions or immune-related adverse reactions must be controlled with a daily dose of 10 mg or less of prednisone or its equivalent, and must be gradually tapered before the next dose). If more than 10 mg of prednisone is taken daily, IMM01 administration must be temporarily discontinued; 4. Not tolerate any traditional Chinese medicine approved for anticancer therapy; 5. No immunization with live or attenuated vaccines will be permitted throughout the study.

[0092] The sample size for statistical analysis is explained as follows:

[0093] The Phase 1b study will use a 3+3 approach for dose escalation, with 3-6 patients in each dose group, and plans call for enrolling more than 15 subjects in the Phase 2 cohort.

[0094] Descriptive statistics will be used for safety data. Dose-limiting toxicities (DLTs) occurring in each treatment group will be studied in the Phase 1b study, and all adverse events (AEs), treatment-related adverse events (TRAEs), AEs leading to death, and AEs leading to treatment discontinuation will be analyzed according to severity (NCI-CTCAE 5.0), system organ class (SOC), and / or preferred term (PT).

[0095] The number of subjects with complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) will be calculated according to RECIST v1.1 or Lugano 2014. Objective response rate (ORR, CR+RR) and disease control rate (DCR, CR+PR+SD) will be determined based on the subject's best overall response. Time to event (time to CR, PR, SD, or PD), DCR, time to response (TTR), and progression-free survival (PFS) will be analyzed using the Kaplan-Meier method.

[0096] The numbers of subjects with iRECIST complete response (iCR), partial response (iPR), stable disease (iSD), unconfirmed progressive disease (iUPD), and confirmed progressive disease (iCPD) will be calculated, and the objective response rates (iORR, iCR + iRR) and disease control rates (iDCR, iCR + iPR + iSD) will be determined based on the subject's best overall response. Time to event (time to CR, PR, SD, or PD), iDCR, time to response (iTTR), and progression-free survival (iPFS) will be analyzed using the Kaplan-Meier method.

[0097] Based on data collected to date, IMM01 does not induce significant hemagglutination, and therefore, IMM01 administration does not require priming or dose ramp-up, making the combination therapy of the present disclosure safer and more convenient. Furthermore, IMM01 has high binding affinity for CD47-expressing tumor cells, and doses of 2.0 mg / kg or less of IMM01 can produce single-agent efficacy in vivo.

[0098] Most importantly, the IMM01 + anti-PD-1 combination achieved an ORR of 66.7% and a DCR of 93.9%, respectively, in cHL patients, suggesting that the disclosed combination therapy may benefit most cHL patients. Because all cHL patients enrolled in the Phase II trial experienced failure of anti-PD-1 therapy, the current combination therapy disclosed herein may be a good option for this patient cohort. Overall, the combination therapy was well tolerated. Fourteen of 33 patients experienced clinically insignificant G3 / 4 TRAEs, with the most common G3 / 4 TRAE being a transient decrease in lymphocyte count. The lymphopenia associated with IMM01 was transient, occurring immediately after IMM01 infusion and recovering to baseline within a few hours to 2–3 days. This phenomenon is thought to be caused by lymphocyte redistribution, with no lymphocyte damage. Furthermore, IMM01 does not cause myelosuppression within the bone marrow. Platelet and hemoglobin decreases were transient, generally returning to baseline within 4 hours to 8 days. Treatment-related hemolytic anemia and permanent discontinuation of the study did not occur.

[0099] The present disclosure will now be further illustrated by the following non-limiting examples. example Example 1 A Phase Ib Dose-Escalation Study of IMM01 + Tislelizumab Combination

[0100] A traditional 3+3 design was used to determine dose escalation of the IMM01 + azacutudube (AZA) combination in the treatment of cHL and to determine dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), and recommended phase 2 doses (RP2Ds).

[0101] Briefly, according to the Phase I clinical trial design, subjects with advanced solid tumors who passed a screening process received either i) tislelizumab (BeiGene) at a fixed dose of 200 mg administered intravenously once every three weeks for one treatment cycle, or ii) IMM01 protein (timdarpacept) in 0.9% saline at doses of 1.0 mg / kg, 1.5 mg / kg, or 2.0 mg / kg administered intravenously once every three weeks for one treatment cycle. Tislelizumab infusions were administered over 60 minutes or longer for the first infusion and, if well tolerated, over 30 minutes or longer for subsequent infusions. IMM01 infusions were administered over 180 ± 15 minutes for the first infusion, 120 ± 15 minutes for the second infusion, and 60 ± 15 minutes for subsequent infusions. If IMM01 and tislelizumab were administered on the same day, IMM01 infusion was scheduled at least 30 minutes after the completion of tislelizumab administration. Treatment was to be discontinued if the patient experienced disease progression / death, unacceptable toxicity, consent withdrawal, loss to follow-up, 48 weeks of treatment, or treatment discontinuation in the investigator's opinion was in the patient's best interest, whichever occurred first.

[0102] Subjects were monitored for the occurrence of adverse events (AEs) (including type, incidence, duration, and severity) and their physical condition (e.g., ECG and ECHO test results) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The pharmacokinetic (PK) properties, immunogenicity, and preliminary antitumor activity of the IMM01 + tislelizumab combination were also measured.

[0103] Tumor assessments will be performed every 6 weeks ± 7 days after the first dose of study drug, and tumor imaging may be arranged for subjects with suspected disease progression or new tumor lesions, or for subjects who discontinue treatment for any reason. Subjects who complete the study will be required to undergo tumor assessments every 12 weeks until disease progression, initiation of new anticancer drug treatment, or death.

[0104] The Phase I trial ended when the last subject withdrew consent, terminated treatment or withdrew from the study, was lost to follow-up or died, completed 48 weeks of treatment, or terminated the study early, whichever occurred first.

[0105] DLT refers to toxicity potentially related to the study drug, including hematologic, nonhematologic, and infusion-related reactions observed within 1 to 21 days after the first dose, and other toxicities resulting in death not attributable to tumor progression. Hematologic toxicities were defined as: 1) Grade 4 neutropenia lasting more than 5 days; 2) Grade 3 or greater neutropenia with fever (neutrophil count ≥ 1.0 × 10); 9 / L or less, body temperature >38.3°C or body temperature >38.0°C for >1 hour), 3) thrombocytopenia (grade 3 or greater thrombocytopenia associated with bleeding or requiring platelet infusion; platelet count >25 × 10 for >24 hours 9 / L), 4) asymptomatic grade 4 thrombocytopenia, 5) grade 4 anemia, and 6) other grade 4 hematologic toxic events. Non-hematologic toxicities were defined as: 1) Grade 3 or greater toxicity to vital organs, including the heart, lungs, gastrointestinal tract, liver, kidneys, and nervous system; 2) Grade 4 or greater non-hematologic toxic events other than a. Grade 3 rash, nausea / vomiting, diarrhea, and / or electrolyte imbalance that can be alleviated to Grade 2 or less within 72 hours after best supportive care; b. Grade 3 fatigue that persists for 7 days or less; c. Grade 3 or less endocrine system disorders that can be controlled with hormone replacement therapy; d. Grade 3 tumor lysis syndrome or related electrolyte imbalance that can be alleviated to Grade 2 or less within 7 days; e. Grade 3 elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and / or alkaline phosphatase (ALP) levels that can be alleviated to Grade 2 or less within 7 days with relative treatment; and 3) Grade 3 cytokine release syndrome that cannot be alleviated to Grade 1 or baseline within 7 days. This includes CRS (Collateral Reaction Syndrome). Infusion-related / allergic reactions (IRRs) are adverse reactions that commonly occur during intravenous infusion of protein drugs and are not considered DLTs, except for grade 4 IRRs. If a grade 4 IRR is observed, treatment for the subject will be discontinued and the subject will need to receive treatment. If more than two subjects experience a grade 4 IRR, enrollment must be paused, and the sponsor management committee (SMC) must discuss whether to discontinue enrollment.

[0106] The MTD is defined as the highest dose at which dose-limiting toxicity (DLT) is observed in 1 / 6 or fewer subjects. To determine a dose level as the MTD, there must be at least 6 subjects with evaluable DLT data. Once the MTD is determined, the MTD is usually used as the RP2D, or a dose level below the MTD can be selected as the RP2D.

[0107] The RP2D was initially determined based on safety, PK, efficacy, and other data collected in the current dose-escalation study, combined with safety, tolerability, and PK / PD data from a dose-escalation study of IMM01 monotherapy for treating lymphoma (this is an unpublished study), and ultimately determined by a Scientific Review Committee (SRC). The dosing regimen of IMM01 at 2.0 mg / kg was ultimately selected as the recommended phase 2 dose (RP2D) for cHL patients, particularly R / R cHL patients. Example 2 Phase II clinical trial of IMM01 plus tislelizumab combination in patients with cHL

[0108] In the Phase II clinical trial, cHL patients have been and are currently enrolled according to the inclusion and exclusion criteria described in the Detailed Description section above. Essentially, cHL patients who have been histologically diagnosed with cHL and have experienced failure of systemic second-line therapy or failure of autologous stem cell transplant (ASCT) have been and are currently enrolled.

[0109] Once enrolled, cHL patients received i) tislelizumab at a fixed dose of 200 mg administered intravenously once every 3 weeks for each 3-week treatment cycle, and ii) IMM01 protein (timdarpacept) at a dose of 2.0 mg / kg administered intravenously once every 3 weeks for each treatment cycle. Tislelizumab infusions were administered over 60 minutes or longer for the first infusion and, if well tolerated, over 30 minutes or longer for subsequent infusions. IMM01 infusions were administered over 180 ± 15 minutes for the first infusion, 120 ± 15 minutes for the second infusion, and 60 ± 15 minutes for subsequent infusions. If IMM01 and tislelizumab were to be administered on the same day, the IMM01 infusion was scheduled to occur at least 30 minutes after the completion of tislelizumab administration.

[0110] Tumor assessments will be performed every 6 weeks ± 7 days after the first dose of study drug, and tumor imaging may be arranged for subjects with suspected disease progression or new tumor lesions, or for subjects who discontinue treatment for any reason. Subjects who discontinue the study are required to undergo tumor assessments every 12 weeks until disease progression, initiation of new anticancer drug treatment, or death.

[0111] Treatment was to be discontinued if a patient experienced disease progression / death, intolerable toxicity, consent withdrawal, loss to follow-up, 48 weeks of treatment, or treatment discontinuation in the investigator's opinion that was in the patient's best interest, whichever occurred first. Example 3 Efficacy of IMM01 (timdarpacept) and tislelizumab combination in patients with R / R cHL

[0112] As of February 19, 2024, 33 patients with R / R cHL had been enrolled and treated with the combination of IMM01 and tislelizumab. All of these patients had previously received at least one anti-PD-1-containing regimen, 14 of whom had resistance to previous tislelizumab treatment, and 21 of whom had resistance to previous other non-tislelizumab PD-1 antibody treatment.

[0113] The baseline characteristics of these patients are summarized in Table 2. Table 2 Baseline characteristics of cHL patients [Table 2]

[0114] Table 3 summarizes the phase II efficacy data recorded as of February 19, 2024. Of the 33 response-evaluable patients, 8, 14, and 9 achieved complete response (CR), partial response (PR), and stable disease (SD), respectively. The objective response rate (ORR) was 66.7%, and the disease control rate (DCR) was 93.9%.

[0115] The time to response (TTR) was approximately 2.1 months. Table 3. Efficacy of IMM01 + tislelizumab combination in patients with R / R cHL [Table 3]

[0116] Patients' individual responses and duration of response (DOR) are shown in Figure 1. After the first dose of study drug, the majority of patients achieved SD at approximately 30-40 days, followed by PR or CR at approximately 80 days, with a small number of patients achieving PR at approximately 30-40 days. Patients' maximum percent change from baseline, calculated as the sum of the products of diameters (SPD) of the lesions, is shown in Figure 2. More than half of these patients experienced a greater than 50% reduction in SPD.

[0117] Of the 14 patients with resistance to tislelizumab (see Table 4), 2 achieved CR, 9 achieved PR, and 3 achieved SD. The ORR was 78.6%, and the DCR was 100%. Of the 21 patients with resistance to other non-tislelizumab PD-1 antibodies (see Table 4), 6 achieved CR, 6 achieved PR, and 7 achieved SD. The ORR was 57.1%, and the DCR was 90.5%. This suggests that the IMM01 + tislelizumab combination may have potent efficacy in treating patients with R / R cHL who have failed previous anti-PD-1 monotherapy. Table 4. Efficacy of IMM01 + tislelizumab combination in cHL patients with resistance to tislelizumab or non-tislelizumab anti-PD-1 [Table 4] Example 4 Safety of IMM01 (timdarpacept) and tislelizumab combination in patients with R / R cHL

[0118] Treatment-related adverse events (TRAEs) observed during this treatment with the IMM01 + tislelizumab combination are summarized in Table 5. Table 5. Treatment-related adverse events in IMM01 + tislelizumab combination therapy [Table 5]

[0119] Overall, the IMM01 + tislelizumab combination was well tolerated. The most common TRAEs (≥20%) were decreased white blood cell count (48.5%), decreased platelet count (42.4%), anemia (33.3%), decreased lymphocyte count (30.3%), and decreased neutrophil count (33.3%). Fourteen of 33 patients (42.4%) had G3 / 4 TRAEs, with decreased lymphocyte count being the most common G3 / 4 TRAE (≥20%).

[0120] Overall, lymphopenia associated with IMM01 was transient, occurring immediately after IMM01 infusion and recovering to baseline within a few hours to 2-3 days. This phenomenon was caused by lymphocyte redistribution, but lymphocytes were not thought to be damaged. IMM01 does not cause myelosuppression within the bone marrow. Decreases in platelets and hemoglobin were transient and generally returned to baseline within 4 hours to 8 days. There were no cases of treatment-related hemolytic anemia or permanent discontinuation of the study. SEQ ID NO: 1 EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISAITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSAPVVSGPAARATPQHEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. SEQ ID NO: 2 EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISAITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSAPVVSGP. SEQ ID NO: 3 AARATPQHEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

[0121] Thus, while preferred embodiments of the invention have been described in detail, it should be understood that the invention defined by the above paragraphs is not limited to the particular details set forth in the above description, as many obvious variations thereof are possible without departing from the spirit or scope of the invention.

Claims

1. 1. A pharmaceutical composition for use in treating classical Hodgkin's lymphoma (cHL) in a subject in need thereof, comprising a recombinant fusion protein, wherein the pharmaceutical composition is administered in combination with an anti-PD-1 antibody, the recombinant fusion protein having a mutated SIRPαD1 domain and a functional IgG1 heavy chain constant region, the mutated SIRPαD1 domain comprising the amino acid sequence of SEQ ID NO:

2.

2. The pharmaceutical composition of claim 1 , wherein the recombinant fusion protein has the amino acid sequence of SEQ ID NO:

1.

3. The pharmaceutical composition of claim 1, wherein the anti-PD-1 antibody is tislelizumab.

4. The treatment comprises: i) administering the recombinant fusion protein at a dose of about 2.0 mg / kg body weight once a week; and ii) the anti-PD-1 antibody at a dose of about 200 mg once every three weeks; The pharmaceutical composition of claim 1, wherein the composition is administered intravenously to the subject.

5. 5. The pharmaceutical composition of claim 4, wherein, when the recombinant fusion protein and the anti-PD-1 antibody are administered on the same day, the recombinant fusion protein is administered at least 30 minutes after administration of the anti-PD-1 antibody is completed.

6. 5. The pharmaceutical composition of claim 4, wherein the recombinant fusion protein is administered by intravenous infusion and the anti-PD-1 antibody is administered by intravenous infusion.

7. The treatment comprises: (a) intravenously administering to the subject about 200 mg of the anti-PD-1 antibody in the form of a composition comprising a pharmaceutically acceptable excipient and the anti-PD-1 antibody; (b) intravenously administering to the subject about 2.0 mg / kg body weight of the recombinant fusion protein in the form of a composition comprising a pharmaceutically acceptable excipient and the recombinant fusion protein; and (c) after steps (a) and (b), repeating step (a) once every three weeks and repeating step (b) once a week.

5. The pharmaceutical composition of claim 4, comprising:

8. 8. The pharmaceutical composition of claim 7, wherein step (b) is performed at least 30 minutes after completing step (a).

9. 8. The pharmaceutical composition of claim 7, wherein, when the recombinant fusion protein and the anti-PD-1 antibody are administered on the same day, the recombinant fusion protein is administered at least 30 minutes after administration of the anti-PD-1 antibody is completed.

10. 10. The pharmaceutical composition of claim 1, wherein the treatment does not include administration of a priming dose of the recombinant fusion protein or a dose ramp-up dose of the recombinant fusion protein to alleviate targeted anemia.

11. The treatment comprises: i) producing an objective response rate of greater than 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% after 24 weeks or longer of said treatment, said objective response rate being defined as the sum of the complete response (CR) rate and the partial response (PR) rate; ii) produces a complete response rate of greater than 20%, 25%, 30%, 35%, 40%, or 45% after 24 weeks or longer of said treatment; or 3. The pharmaceutical composition of claim 1, wherein iii) after 24 weeks or longer of said treatment, the composition produces a disease control rate of greater than 85%, 90%, or 95%, wherein the disease control rate is defined as the sum of the complete response (CR) rate, the partial response (PR) rate, and the stable disease (SD) rate.

12. i) Treatment-related hemolytic anemia is likely to occur in 5% or 10% or less of treated subjects; or ii) The pharmaceutical composition of claim 1, wherein the likelihood of treatment discontinuation due to treatment-related adverse effects is less than 15% or 20% of treated subjects.

13. The pharmaceutical composition of claim 1 , wherein the subject has relapsed or refractory cHL.

14. The pharmaceutical composition of claim 13, wherein the subject has experienced failure of a previous anti-PD-1 therapy.

15. 1. A pharmaceutical composition comprising: i) a recombinant fusion protein; and ii) an anti-PD-1 antibody, wherein the recombinant fusion protein has a mutated SIRPαD1 domain and a functional IgG1 heavy chain constant region, wherein the mutated SIRPαD1 domain comprises the amino acid sequence of SEQ ID NO: 2, and the anti-PD-1 antibody is tislelizumab.

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