Antineoplastic combinations

Abstract

Antineoplastic Combinations The present disclosure provides a combination comprising: (a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and (b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises: (c) at least one polyether-polyester copolymer, wherein the copolymer has the formula: B(A)n wherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and (d) at least one organic solvent. Therapeutic methods / uses for treating solid tumors are also provided as are products and kits of parts comprising the combinations / compositions of the present disclosure.

Description

Antineoplastic CombinationsFIELD

[0001] The present invention relates to combinations of a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof, and a second composition comprising at least one small-molecule antineoplastic agent as defined herein. At least one of the first composition and second composition further comprises at least one polyetherpolyester copolymer as defined herein and at least one organic solvent so as to provide a sustained release of the antineoplastic antibody and / or small-molecule antineoplastic agent. The combinations of the present disclosure are useful in the treatment of solid tumors.BACKGROUND

[0002] Although there have been remarkable advances in cancer therapy in recent years, in many cases long-term outcomes remain poor, particularly for advanced stage, metastatic, and / or unresectable cancers. For example, melanoma is the most aggressive form of skin cancer when metastasized, having an overall survival (OS) rate of 32% (American Cancer Society). While early-stage melanomas can often be cured with surgery, more advanced melanomas can be much harder to treat.

[0003] First-line treatments for unresectable and metastatic melanoma include anti-PD1 and / or anti-CTLA-4 immunotherapies (typically for triple-negative melanoma and melanoma positive for NRAS mutations), or targeted therapies (e.g. BRAF and / or MEK inhibitors for BRAF positive tumors).

[0004] About half of all melanomas are positive for BRAF mutations, which are the most frequent type of driver mutation in melanoma followed by NRAS mutations, which are present in around 25% of patients. In both cases, the mutations lead to a hyperactivation of the MAPK signaling pathway, promoting melanoma progression (Randic et al., “NRAS mutant melanoma: towards better therapies", Anti-tumour Treatment (2021); Alqathama et al., “BRAF in malignant melanoma progression and metastasis: potentials and challenges" American Journal of Cancer Research (2020)).

[0005] Examples of immunotherapies include programmed death receptor-1 (PD-1) blocking antibodies such as KEYTRUDA®, a pembrolizumab solution for IV perfusion, or OPDIVO®, a nivolumab solution for IV perfusion, or a combination of such antibodies. Examples of anti-BRAF targeted therapies include ZELBORAF®, a vemurafenib tablet for oral use, TAFINLAR®, a dabrafenib capsule for oral use or BRAFTOVI®, an encorafenib capsule for oral use. Examples of anti-MEK targeted therapies include M EKIN 1ST®, a trametinib tablet for oral use, COTELLIC®, a cobimetinib tablet for oral use, or MEKTOVI®, a binimetinib tablet for oral use. The foregoing oral therapies typically require daily or even twice daily intake and are often combined for increased efficacy.

[0006] Nonetheless, the patient response rate to immunotherapies is often low (e.g. around 40%) and unpredictable. On the other hand, resistance to targeted therapies is highly prevalent and emerges in almost 100% of cases post-treatment.

[0007] Combination therapies have therefore become an important part of the clinical armamentarium for the treatment of cancers, and in particular late-stage and / or metastasized cancers. The aim with combination therapies is to improve progression-free survival (PFS) and / or overall survival (OS) relative to monotherapies. For example, combined therapeutic approaches comprising the co-administration of immunotherapies with targeted therapies have been developed, e.g. for melanoma. These have been found to be more effective than immunotherapy or targeted therapy alone, however such combinations are associated with a considerable treatment burden, for instance due to increased drug toxicity and / or side-effects. The subject receiving combination therapy is also confronted with an increased burden in terms of administration of the respective therapies comprised in the combination therapy, which may require more gruelling dosage regimes requiring e.g. additional visits and / or time in clinical settings, in particular for parenteral administration. Such treatment burdens can often lead to suspension or discontinuation of treatment (Jenkins et al., “Treatment of Advanced Melanoma in 2020 and Beyond", Journal of Investigative Dermatology (2021)).

[0008] In 2016, a Phase I study in patients with advanced melanoma highlighted an interesting anti-tumor effect of flanvotumab, also known as IMC-20D7S, a monoclonal antibody (mAb) targeting Tyrosinase-Related Protein-1 (TYRP1 , also known Trp1 or gp75). TYRP1 is a transmembrane glycoprotein that is specifically and abundantly expressed in melanocytes and melanoma cells. Flanvotumab was first described in US 7951370 B2. Flanvotumab is the human equivalent of murine TA99, a mAb targeting both human and mouse TYRP1. Tumor antigen (TA)-targeting monoclonal antibodies have the unique capacity to specifically target cancer cells and to kill them through FcyR-dependent mechanisms such as antibodydependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, the modest clinical activity observed in patients with advanced melanomafollowing IV repeated administration every 2 to 3 weeks at a dose of up to 30 mg / kg of flanvotumab (see Khalil et al. “An Open-label, Dose-Escalation Phase 1 Study of anti-TYRP1 monoclonal antibody IMC-20D7S for patients with relapsed or refractory melanoma” Clinical Cancer Research (2016)), led to the further study of TYRP1 targeting mAb in combination with other immunotherapies.

[0009] A short treatment of B16F10 grafted mice consisting of repeated intraperitoneal injections of TA99 and CD279, an anti-PD1 antibody, resulted in a synergistic effect as evidenced by the delayed tumor growth and increased survival rate compared to group treated with TA99 alone. Despite this enhanced anti-tumor effect, no complete tumor regression was however achieved in mice (See They et al. “PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody” Oncoimmunology (2017)).

[0010] Similarly, other studies demonstrated enhanced tumor-targeting antibody therapy when co-administering TA99 with immune-activating compounds, such as anti-PD1 and anti-CTLA4 monoclonal antibodies (see Benonisson et al. “High FcyR Expression on Intratumoral Macrophages Enhances Tumor-Targeting antibody therapy” The journal of Immunology (2021)).

[0011] WO 2001 010 / 416 A1 discloses a method of delivering a chemotherapeutic agent to a solid tumor via a localized administration of a long-acting composition comprising polymeric microparticles.

[0012] Other long-acting compositions, such as silica nanoparticles or hydrogels, have also been tested in the last decades for enhancing the efficacy of immunotherapy or immune check point in controlling tumor growth (e.g. Kim et al. “Nanoparticle delivery of recombinant IL-2 (BALLkine-2) achieves durable tumor control with less systemic adverse effects in cancer immunotherapy” Biomaterials (2022), or Samlowski et al. “ReGel® polymer-based delivery of lnterleukin-2 as a Cancer Treatment” Journal of Immunotherapy (2006), or Chung et al. “Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies,” Journal of Controlled Release (2020)).

[0013] There remains, however, a need to overcome the above challenges with improved combination therapies that provide greater efficiency of treatment and reduce treatment burdens such as systemic drug toxicity. The present disclosure meets this need with the various aspects and embodiments defined herein.SUMMARY

[0014] In one aspect, the present disclosure provides a combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0015] In various embodiments, the combination as defined herein is for use in treating a solid tumor in a subject.

[0016] A further aspect of the present disclosure provides a pharmaceutical composition comprising:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), eachA represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0017] A further aspect of the present disclosure provides a pharmaceutical composition comprising:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0018] In various embodiments, the pharmaceutical compositions according to the foregoing aspects may be for use in treating a solid tumor in a subject.

[0019] In another aspect the present disclosure provides a method of treating a solid tumor in a subject, the method comprising administering to the subject:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0020] In various embodiments of the method, the first composition and the second composition are administered separately, sequentially or simultaneously to the subject.

[0021] In another aspect the present disclosure provides a product comprising a combination of:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; as a combined preparation for simultaneous, separate or sequential use in treating a tumor; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0022] In another aspect the present disclosure provides a kit comprising:(A) a prefilled syringe comprising a first injectable composition, wherein the injectable composition comprises:- at least one antineoplastic antibody or an antigen-binding fragment thereof, or at least one small-molecule antineoplastic agent;- at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.(B) at least one needle; and(C) instructions for use.

[0023] In another aspect the present disclosure provides the use of (a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof in combination with (b) a second composition comprising at least one small-molecule antineoplastic agent in the manufacture of a medicament for treating a solid tumor in a subject, wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0024] In another aspect the present disclosure provides the use of (b) a second composition comprising at least one small-molecule antineoplastic agent in combination with (a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a solid tumor in a subject, wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0025] In another aspect the present disclosure provides the use of a pharmaceutical composition in the manufacture of a medicament for treating a solid tumor in a subject, wherein said pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0026] In another aspect the present disclosure provides the use of a pharmaceutical composition in the manufacture of a medicament for treating a solid tumor in a subject, wherein said pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0027] These aspects and embodiments are set out in the appended independent and dependent claims. It will be appreciated that features of the dependent claims may be combined with each other and with features of the independent claims in combinations other than those explicitly set out in the claims. Furthermore, the approaches described herein are not restricted to specific embodiments such as those set out below, but include and contemplate any combinations of features presented herein.

[0028] The foregoing and other objects, features, and advantages of the present disclosure will appear more fully hereinafter from a consideration of the detailed description that follows along with the accompanying drawings. It is to be expressly understood, however, that the drawings are for illustrative purposes and are not to be construed as defining the limits of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a schematic diagram of the current understanding of the MAPK pathway exemplified for melanomas. In particular, NRAS and BRAF are highlighted as being common driver mutations in melanoma (percentages indicate frequency of occurrence of mutations in NRAS and BRAF in melanomas).

[0030] Figure 2 discloses results from in vitro release tests performed with different imiquimod formulations. The data show that different release kinetics can be obtained depending on the formulation composition.

[0031] Figure 3 discloses results from in vitro release tests performed with two trametinib formulations. The data show that different release kinetics can be obtained depending on the formulation composition.

[0032] Figure 4 discloses the release profiles obtained after subcutaneous injection in mice of two imiquimod formulations. Sustained release of imiquimod was obtained over a period of about a month for both formulations with a much higher amount of imiquimod initially released (up to 4 days post-injection) for the formulation comprising the HCI salt.

[0033] Figure 5 discloses the overall survival over time following administration of monotherapies or combination therapy. The highest survival rate was obtained with the combination therapy, supporting a synergistic effect of the combination therapy.

[0034] Figure 6 discloses the evolution of tumor size over time. While in the control group the maximal defined size was reached for all animals within about 3 weeks following tumor-cells graft, 3 out of 8 animals and 5 out of 8 animals did not present any increase in tumor size after about 2 months with the TA99 monotherapy and TA99+imiquimod combination therapy respectively.

[0035] Figure 7 compares the evolution of tumor size over time after tumor cell grafting between naive mice of a control group, and surviving mice from the previous study. For the surviving mice, tumor cells were grafted on the opposite flank. Results show a delayed tumor appearance compared to the control group for the surviving mice that were previously treated with TA99 monotherapy or combination therapy.

[0036] Figure 8 discloses the overall survival over time following administration of TA99 as repeated IP injections or as a single peritumoral injection of a long-acting formulation compared to control groups (PBS and polymer vehicle). The data show that, for a same administered dose, a single peritumoral injection of a long-acting TA99 formulation provides similar results to 6 repeated TA99 injections, improving the survival rate compared to control groups.

[0037] Figure 9 shows the evolution of tumor size over time. The data show a delayed tumor growth with both TA99 groups compared to control groups.

[0038] Figure 10 shows TA99 plasma concentrations measured at 15 and 28 days following a single peritumoral injection of a long-acting TA99 F2 formulation or following 6 repeated intraperitoneal injections of TA99 aqueous solutions.

[0039] Figure 11 discloses the evolution of tumor size after administration of monotherapies or combination therapy. A delayed tumor appearance were obtained with the combination therapy comprising a single imiquimod peritumoral administration, supporting a synergistic effect of the combination therapy when the imiquimod formulation is administered peritumoraly.

[0040] Figure 12 discloses the overall survival over time after administration of monotherapies or combination therapy. An improved survival rate was obtained with the combination therapy comprising a single imiquimod peritumoral administration, supporting a synergistic effect of the combination therapy when the imiquimod formulation is administered parenterally.

[0041] Figure 13 discloses the imiquimod plasmatic concentration over time from mice administered imiquimod topically or subcutaneously. Higher concentrations were measured in the mice administered imiquimod topically.

[0042] Figure 14 discloses the overall survival over time following the combination of TA99 IP administration with the subcutaneous administration of F20-lm nearby the tumor site on the right flank or on the opposite flank.

[0043] Figure 15 discloses the overall survival over time following administration of monotherapies or combination therapy. The highest survival rate was obtained with the combination therapy comprising TA99 IP administration with F1-Dab / Trab peritumoral administration.

[0044] Figure 16 discloses discloses the percentages of dabrafenib and trametinib left in depot reecovered from mice administered a single dabrafenib / trametinib combined peritumoral administration.DETAILED DESCRIPTION

[0045] While various exemplary embodiments are described or suggested herein, other exemplary embodiments utilizing a variety of methods and materials similar or equivalent to those described or suggested herein are encompassed by the general inventive concepts. Those aspects and features of embodiments which are implemented conventionally may not be discussed or described in detail in the interests of brevity. It will thus be appreciated that aspects and features of apparatus and methods described herein which are not described in detail may be implemented in accordance with any conventional techniques for implementing such aspects and features.

[0046] As used herein, the expressions “combination of’ and “in combination with" cover separate, sequential and simultaneous administration of the compositions defined herein. Unless specified to the contrary, the expressions are also intended to exclude any additional actives, e.g. “a combination comprising (a) a first combination comprising at least one antineoplastic antibody or an antigen-binding fragment thereof and (b) a second compositioncomprising at least one small-molecule antineoplastic agent” means that the defined first and second compositions are administered separately, sequentially or simultaneously but that no other actives, i.e. antineoplastic antibodies and small-molecule antineoplastic agents, are administered.

[0047] When the compositions are administered sequentially, either the first or second composition may be administered first. When administration is simultaneous, the compositions may be administered as a single combined composition (e.g. comprising the first and second composition as defined herein) or as different pharmaceutical compositions. In preferred embodiments, the compositions are administered sequentially or simultaneously.

[0048] As described herein in further embodiments, the combinations of the present disclosure may comprise at least one further composition, for example a third composition comprising at least one small-molecule antineoplastic agent or a third composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof. When such compositions are administered sequentially, any of the first, second, or third composition may be administered first. Where the first composition is administered first, the second composition may be administered second, or alternatively the third composition may be administered second. Where the second composition is administered first, the first composition may be administered second, or the third composition may be administered second. Where the third composition is administered first, the first composition may be administered second, or the second composition may be administered second. When administration is simultaneous, the compositions may be administered as a single combined composition (e.g. comprising first, second, and third compositions as defined herein) or as different pharmaceutical compositions. In preferred embodiments, the compositions are administered sequentially or simultaneously.

[0049] In various embodiments, the second administration may be performed within the same day as the first administration. For example, the first administration may be performed in the morning and the second administration performed in the afternoon of the same day. Where there are e.g. third administrations, the first administration may be performed in the morning, the second administration may be performed around mid-day of the same day, and the third administration may be performed in the afternoon of the same day. Practitioners in the art will be able to select suitable administration schedules based on their common general knowledge and general clinical practice.

[0050] As used herein, the term “antineoplastic” refers to agents used to treat cancer. Antineoplastic agents may also be described as anticancer drugs, anti-tumoral drugs orchemotherapeutic agents and the terms may be used interchangeably within the context of the present disclosure. Cancer is a disorder associated with abnormal cell proliferation and antineoplastic agents such as those described herein aim, either directly or indirectly and via different mechanisms, at controlling such abnormal cell proliferation. Said terms are commonly used in the art and a person skilled in the art of the present disclosure will be able to identify therapeutics belonging to this class.

[0051] Non-limiting examples of antineoplastic agents include:

[0052] Alkylating Agents: e.g. Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurbinectedin, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedin;

[0053] Platinum Coordination Complexes: e.g. Carboplatin, Cisplatin, Oxaliplatin;

[0054] Cytotoxic antibiotics: e.g. Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Valrubicin;

[0055] Antimetabolites: e.g. Antifolates (e.g. Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate); Purine Analogues (e.g. Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Thioguanine); Pyrimidine Analogues (e.g. Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, Trifluridine / Tipracil)

[0056] Biologic Response Modifiers: e.g. Aldesleukin (IL-2), Denileukin Diftitox, Interferon Gamma

[0057] Histone Deacetylase Inhibitors: e.g. Belinostat, Panobinostat, Romidepsin, Vorinostat

[0058] Hormonal Agents: e.g. Antiandrogens (Abiraterone, Apalutamide, Bicalutamide, Cyproterone, Enzalutamide, Flutamide, Nilutamide); Antiestrogens including Aromatase Inhibitors (e.g. Anastrozole, Exemestane, Fulvestrant, Letrozole, Raloxifene, Tamoxifen, Toremifene); Gonadotropin Releasing Hormone Analogues (e.g. Degarelix, Goserelin, Histrelin, Leuprolide, Relugolix, Triptorelin); Peptide Hormones (e.g. Lanreotide, Octreotide, Pasireotide);

[0059] Monoclonal Antibodies: e.g. Alemtuzumab, Atezolizumab, Avelumab, Bevacizumab, Blinatumomab, Brentuximab, Cemiplimab, Cetuximab, Daratumumab, Dinutuximab,Dostarlimab, Durvalumab, Elotuzumab, Fianlimab, Gemtuzumab, Inotuzumab Ozogamicin, Ipilimumab, Mogamulizumab, Moxetumomab Pasudotox, Necitumumab, Nivolumab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Relatlimab, Rituximab, Teclistamab, Tiragolumab, Tositumomab, Trastuzumab, Tremelimumab, Vibostolimab;

[0060] Protein Kinase Inhibitors: e.g. Abemaciclib, Acalabrutinib, Adagrasib, Afatinib, Alectinib, Alpelisib, Axitinib, Binimetinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Ponatinib, Regorafenib, Ribocicib, Rucaparib, Ruxolitinib, Selumetinib, Sonidegib, Sorafenib, Sotorasib, Sunitinib, Talazoparib, Temuterkib, Trametinib, Vandetanib, Vemurafenib, Vismodegib, Zanubrutinib;

[0061] Taxanes: e.g. Cabazitaxel, Docetaxel, Paclitaxel;

[0062] Topoisomerase Inhibitors: e.g. Etoposide, Irinotecan, Teniposide, Topotecan;

[0063] Vinca Alkaloids: e.g. Vinblastine, Vincristine, Vinorelbine;

[0064] Miscellaneous: e.g. Asparaginase (Pegaspargase), Belzutifan, Bexarotene, Cedazuridine, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus, Thalidomide, Venetoclax.

[0065] As noted above, antineoplastic agents may be used to directly or indirectly control abnormal cell proliferation. Thus, the antineoplastic agents of the present disclosure also include immunotherapies that exert their effect on the immune system of the subject in need of treatment and thereby activate and / or potentiate a host immune response to the cancer.

[0066] Further examples of antineoplastic agents include cytokine-related therapies, immune cell-based therapies (such as chimeric antigen receptor T cell (CAR-T) therapies), cancer vaccines (active and passive), antibody-drug conjugates, bispecific antibodies, oncolytic viruses, and other immunity-based technologies.

[0067] Specific antineoplastic agents of particular use in the compositions described herein are described in more detail in the following sections. However, the teachings under each section are not limited to the section in which they are found.

[0068] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0069] In this specification, unless otherwise stated, the term "about" modifying the quantity of a component refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making concentrates, mixtures or solutions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the materials employed, or to carry out the methods; and the like. The term “about” also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term "about", the claims include equivalents to the quantities.

[0070] The ranges provided herein provide exemplary amounts of each of the components. Each of these ranges may be taken alone or combined with one or more other component ranges.

[0071] As used herein, wt% means “weight percentage” as the basis for calculating a percentage. Unless indicated otherwise, all % values are calculated on a weight basis, and are provided with reference to the total weight of the product in which the substance is present.

[0072] The general inventive concept is centred on providing combinations and compositions that provide a sustained release of at least one antineoplastic antibody or an antigen-binding fragment thereof and / or at least one small-molecule antineoplastic agent.

[0073] In a first aspect, the present disclosure provides a combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0074] It has been found that the compositions disclosed herein comprising at least one polyether-polyester copolymer according to any of the embodiments described herein provide a sustained release of the small-molecule antineoplastic agent and / or antineoplastic antibody or antigen-binding fragment thereof. Such compositions have been found to advantageously reduce treatment burden and / or systemic toxicity while providing at least comparable efficacy. In particular, combinations comprising said compositions as described herein may have at least comparable if not better efficacy to existing treatments and dosage regimens while reducing treatment burden, improving patient compliance and / or reducing systemic toxicity.

[0075] For ease of reference, these and further features of the present invention are now discussed under appropriate section headings. However, the teachings under each section are not limited to the section in which they are found. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure belongs.Small-molecule antineoplastic agent

[0076] The second composition as described herein comprises at least one small-molecule antineoplastic agent.

[0077] As used herein, the term “small-molecule” takes its normal meaning in the art, namely an organic molecule having a molecular weight of 1000 Da or less. Thus, the term “smallmolecule” does not include biologies such as proteins (e.g. antibodies), polynucleotides, vaccines, and cell-based therapeutics.

[0078] The small-molecule antineoplastic agent is not necessarily limited and a person of skill in the art will be able to identify suitable small-molecule antineoplastic agents on the basis of their common general knowledge.

[0079] Non-limiting examples of small-molecule antineoplastic agents include the following:

[0080] Alkylating Agents: e.g. Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurbinectedin, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedin;

[0081] Platinum Coordination Complexes: e.g. Carboplatin, Cisplatin, Oxaliplatin;

[0082] Cytotoxic antibiotics: e.g. Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Valrubicin;

[0083] Antimetabolites: e.g. Antifolates (e.g. Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate); Purine Analogues (e.g. Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Thioguanine); Pyrimidine Analogues (e.g. Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, Trifluridine / Tipracil)

[0084] Histone Deacetylase Inhibitors: e.g. Belinostat, Panobinostat, Romidepsin, Vorinostat

[0085] Hormonal Agents: e.g. Antiandrogens (Abiraterone, Apalutamide, Bicalutamide, Cyproterone, Enzalutamide, Flutamide, Nilutamide); Antiestrogens including Aromatase Inhibitors (e.g. Anastrozole, Exemestane, Fulvestrant, Letrozole, Raloxifene, Tamoxifen, Toremifene);

[0086] Protein Kinase Inhibitors: e.g. Abemaciclib, Acalabrutinib, Adagrasib, Afatinib, Alectinib, Alpelisib, Asciminib, Avapritinib, Axitinib, Binimetinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Capmatinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Mobocertinib, Momelotinib, Neratinib, Netarsudil, Nilotinib, Nintedanib, Niraparib, Olaparib, Osimertinib, Pacritinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Pirtobrutinib, Ponatinib, Pralsetinib, Quizartinib, Regorafenib, Ribocicib, Ripretinib, Rucaparib, Ruxolitinib, Selpercatinib, Selumetinib, Sonidegib, Sorafenib, Sotorasib, Sunitinib, Talazoparib, Temuterkib, Tepotinib, Tivozanib, Trametinib, Trilaciclib, Tucatinib, Vandetanib, Vemurafenib, Vismodegib, Zanubrutinib;

[0087] Taxanes: e.g. Cabazitaxel, Docetaxel, Paclitaxel;

[0088] Topoisomerase Inhibitors: e.g. Etoposide, Irinotecan, Teniposide, Topotecan;

[0089] Vinca Alkaloids: e.g. Vinblastine, Vincristine, Vinorelbine;

[0090] Miscellaneous: e.g. Belzutifan, Bexarotene, Cedazuridine, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus, Thalidomide, Venetoclax.

[0091] Small-molecule antineoplastic agents may be divided into two categories: conventional or classical chemotherapies that generally only have limited selectivity for tumor cells by virtue of their increased proliferation rate, and targeted therapies, e.g. small-molecule inhibitors selective for a particular extracellular or intracellular target protein, e.g. a protein only expressed / activated in tumor cells or that is over-expressed in tumor cells.

[0092] In preferred embodiments, the at least one small-molecule antineoplastic agent comprises an immune response modifier and / or a protein kinase inhibitor. In further embodiments, the at least one small-molecule antineoplastic agent is selected from immune response modifiers, protein kinase inhibitors, and combinations thereof.

[0093] As used herein, the term “immune response modulator” is a term in the art. Immune response modulators act by stimulating certain aspects of the immune system as well as suppressing certain other aspects. An immune response modifier may alter the level of one or more immune regulatory molecules, e.g., cytokines or co-stimulatory markers, when administered to responsive cell. Representative immune response modulators include, for example, the small organic molecules, purine derivatives, small heterocyclic compounds, amide derivatives, and oligonucleotides. In the present disclosure, the immune response modulator is a small-molecule. Further non-limiting examples of immune response modulators include those disclosed in U.S. Pat. Nos. 4,689,338; 4,929,624; 5,266,575; 5,268,376;5,346,905; 5,352,784; 5,389,640; 5,446,153; 5,482,936; 5,756,747; 6,110,929; 6,194,425;6,331 ,539; 6,376,669; 6,451 ,810; 6,525,064; 6,541 ,485; 6,545,016; 6,545,017; 6,573,273;6,656,938; 6,660,735; 6,660,747; 6,664,260; 6,664,264; 6,664,265; 6,667,312; 6,670,372;6,677,347; 6,677,348; 6,677,349; 6,683,088; 6,756,382; 6,797,718; 6,818,650; and 7,7091 ,214; U.S. Patent Publication Nos. 2004 / 0091491 ; 2004 / 0176367; and 2006 / 0100229; and International Publication Nos. WO 2005 / 18551 , WO 2005 / 18556, WO 2005 / 20999, WO 2005 / 032484, WO 2005 / 048933, WO 2005 / 048945, WO 2005 / 051317, WO 2005 / 051324, WO 2005 / 066169, WO 2005 / 066170, WO 2005 / 066172, WO 2005 / 076783, WO 2005 / 079195, WO 2005 / 094531 , WO 2005 / 123079, WO 2005 / 123080, WO 2006 / 009826, WO 2006 / 009832, WO2006 / 026760, WO 2006 / 028451 , WO 2006 / 028545, WO 2006 / 028962, WO 2006 / 029115, WO 2006 / 038923, WO 2006 / 065280, WO 2006 / 074003, WO 2006 / 083440, WO 2006 / 086449, WO 2006 / 091394, WO 2006 / 086633, WO 2006 / 086634, WO 2006 / 091567, WO 2006 / 091568, WO 2006 / 091647, WO 2006 / 093514, and WO 2006 / 098852.

[0094] Additional examples of small molecule IRMs include certain purine derivatives (such as those described in U.S. Pat. Nos. 6,376,501 , and 6,028,076), certain imidazoquinoline amide derivatives (such as those described in U.S. Pat. No. 6,069,149), certain imidazopyridine derivatives (such as those described in U.S. Pat. No. 6,518,265), certain benzimidazole derivatives (such as those described in U.S. Pat. No. 6,387,938), certain derivatives of a 4-aminopyrimidine fused to a five membered nitrogen containing heterocyclic ring (such as adenine derivatives described in U.S. Pat. Nos. 6,376,501 ; 6,028,076 and 6,329,381 ; and in WO 02 / 08905), certain 3-p-D-ribofuranosylthiazolo[4,5-d]pyrimidine derivatives (such as those described in U.S. Publication No. 2003 / 0199461), and certain small molecule immuno-potentiator compounds such as those described, for example, in U.S. Patent Publication No. 2005 / 0136065.

[0095] Particularly preferred immune response modulators are toll-like receptor (TLR) agonists. Thus, in various embodiments, the at least one small-molecule antineoplastic agent comprises a TLR agonist and / or a protein kinase inhibitor. In further embodiments, the at least one small-molecule antineoplastic agent is selected from TLR agonists, protein kinase inhibitors, and combinations thereof.

[0096] In preferred embodiments, the at least one small-molecule antineoplastic agent comprises a TLR agonist. Particularly preferred TLR agonists include TLR-7, TLR-8 and TLR- 7 / 8 agonists, where “TLR-7 / 8” will be understood by a person skilled in the art to refer to agents acting agonistically on both TLR-7 and TLR-8.

[0097] Examples of TLR-7, TLR-8 and TLR-7 / 8 agonists include, but are not limited to imiquimod, resiquimod, motolimod, and pharmaceutically acceptable derivatives thereof. In various embodiments, the small-molecule anti-neoplastic agent comprises imiquimod, resiquimod, motolimod, or a pharmaceutically acceptable derivative thereof. In further embodiments, the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0098] In various embodiments, the small-molecule antineoplastic agent comprises or is a protein kinase inhibitor. Protein kinase inhibitors are the largest group of targeted small-molecule antineoplastic agents. Protein kinase inhibitors include inhibitors targeting: nonreceptor protein tyrosine kinases, receptor protein tyrosine kinases, and protein serine / threonine kinases, as well as dual-specificity protein kinases. Protein kinase inhibitors may be selective kinase inhibitors or multikinase inhibitors. Multi kinase inhibitors exert anticancer (antineoplastic) activity by repressing multiple protein kinases in the tumor.

[0099] The protein kinase inhibitor of the present disclosure is not necessarily limited. In various embodiments, the protein kinase inhibitor comprises or is selected from Abemaciclib, Acalabrutinib, Adagrasib, Afatinib, Alectinib, Alpelisib, Asciminib, Avapritinib, Axitinib, Binimetinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Capmatinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Mobocertinib, Momelotinib, Neratinib, Netarsudil, Nilotinib, Nintedanib, Niraparib, Olaparib, Osimertinib, Pacritinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Pirtobrutinib, Ponatinib, Pralsetinib, Quizartinib, Regorafenib, Ribocicib, Ripretinib, Rucaparib, Ruxolitinib, Selpercatinib, Selumetinib, Sonidegib, Sorafenib, Sotorasib, Sunitinib, Talazoparib, Temuterkib, Tepotinib, Tivozanib, Trametinib, Trilaciclib, Tucatinib, Vandetanib, Vemurafenib, Vismodegib, Zanubrutinib and combinations thereof.

[0100] In preferred embodiments, the at least one small-molecule antineoplastic agent comprises an inhibitor of at least one component of the mitogen activated protein kinase (MAPK) pathway (also known as the MAPK / ERK pathway, or Ras-Raf-MEK-ERK pathway). A schematic summary of the MAPK pathway is shown in Figure 1. The MAPK pathway is understood to play an important role in regulating cell cycle entry and proliferation. In many cancers (e.g. melanoma), a defect in the MAPK pathway leads to uncontrolled growth and thus there are multiple antineoplastic agents targeting steps in said pathway.

[0101] Most inhibitors targeting the MAPK pathway target MEK, RAF and / or RAS. Thus, in further embodiments, the inhibitor inhibits MEK, RAF and / or RAS.

[0102] Particularly preferred protein kinase inhibitors targeting the MAPK pathway include, but are not limited to, vemurafenib, dabrafenib, encorafenib, trametinib, cobimetinib, binimetinib, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0103] In various embodiments, the protein kinase inhibitor comprises or is a RAF inhibitor, in particular a B-RAF inhibitor. Mutations in BRAF, such as at V600, are associated with several cancers such as melanoma, hairy cell leukemia, non-Hodgkin lymphoma, thyroid cancer, ovarian cancer, lung adenocarcinoma, colorectal cancer and certain brain cancers including glioblastoma, pilocytic astrocytoma, and pediatric low-grade glioma.

[0104] Thus, in various embodiments, the small-molecule antineoplastic agent comprises dabrafenib, encorafenib, or a pharmaceutically acceptable derivative thereof. In further embodiments, the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof.

[0105] In further preferred embodiments, the protein kinase inhibitor is dabrafenib or a pharmaceutically acceptable derivative thereof.

[0106] In other further preferred embodiments, the protein kinase inhibitor is encorafenib or a pharmaceutically acceptable derivative thereof.

[0107] In various embodiments, the protein kinase inhibitor comprises or is a MEK inhibitor. In particular, MEK inhibitors may inhibit MEK1 and / or MEK2. MEK inhibitors are particularly useful for the treatment of BRAF-mutated melanoma and KRAS / BRAF mutated colorectal cancer.

[0108] Thus, in various embodiments, the small-molecule antineoplastic agent comprises trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In further embodiments, the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivative thereof

[0109] In further preferred embodiments, the protein kinase inhibitor is trametinib or a pharmaceutically acceptable derivative thereof.

[0110] In other further preferred embodiments, the protein kinase inhibitor is cobimetinib or a pharmaceutically acceptable derivative thereof.

[0111] In other further preferred embodiments, the protein kinase inhibitor is binimetinib or a pharmaceutically acceptable derivative thereof.

[0112] In other embodiments, the protein kinase inhibitor targeting the MAPK pathway comprises or is an ERK inhibitor. For example, the ERK inhibitor may be temuterkib (LY- 3214996).

[0113] In other embodiments, the small-molecule antineoplastic agent is a RAS inhibitor. For example, the RAS inhibitor may be adagrasib or sotorasib.

[0114] In some embodiments, the small-molecule antineoplastic agent may consist of a protein kinase inhibitor as defined by any of the embodiments detailed herein above. For instance, a protein kinase inhibitor according to any of the embodiments disclosed herein may be the sole small-molecule antineoplastic agent (e.g. the sole active pharmaceutical ingredient) in the second composition of the combination disclosed herein. In further embodiments, a protein kinase inhibitor according to any of the embodiments disclosed herein may be the sole small-molecule antineoplastic agent in the combination disclosed herein.

[0115] However, combinations of RAF and MEK inhibitors, for example, may have increased efficacy over the respective monotherapies. For instance, combinations of BRAF and MEK inhibitors are indicated for BRAF-mutant melanoma, in particular BRAF V600-mutated melanoma. Thus, in alternative embodiments, the protein kinase inhibitor may comprise a first protein kinase inhibitor and a second protein kinase inhibitor, preferably wherein the first protein kinase inhibitor and second protein kinase inhibitor are different. More preferably, the first protein kinase inhibitor is a RAF inhibitor (more preferably a BRAF inhibitor) and the second protein kinase inhibitor is a MEK inhibitor.

[0116] Accordingly, in various embodiments the protein kinase inhibitor comprises (i) a first protein kinase inhibitor selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof, and (ii) a second protein kinase inhibitor selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0117] In particularly preferred embodiments, the first protein kinase inhibitor is dabrafenib or a pharmaceutically acceptable derivative thereof and the second protein kinase inhibitor is trametinib or a pharmaceutically acceptable derivative thereof.

[0118] In another particularly preferred embodiment, the first protein kinase inhibitor is encorafenib or a pharmaceutically acceptable derivative thereof and the second protein kinase inhibitor is binimetinib or a pharmaceutically acceptable derivative thereof.

[0119] The first protein kinase inhibitor and the second protein kinase inhibitor according to any of the embodiments disclosed above are preferably comprised in the same composition, e.g. the second composition of the combinations disclosed herein. Alternatively, the first protein kinase inhibitor and the second protein kinase inhibitor may be comprised in differentcompositions, for example in a combination for simultaneous, separate or sequential administration as further described herein below.

[0120] As used herein the term “pharmaceutically acceptable derivative" means: (a) pharmaceutically acceptable salts; and / or (b) solvates (including hydrates).

[0121] Pharmaceutically acceptable salts of the compounds included in the combinations of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977).

[0122] Suitable acid addition salts include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a- hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts (e.g. benzenesulfonate, methyl-, bromo- or chlorobenzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts. Suitable base salts include metal salts, e.g. sodium, calcium, and amine salts.

[0123] For example, dabrafenib is available commercially as dabrafenib mesylate, trametinib is commercially available as trametinib dimethyl sulfoxide, cobimetinib is available as cobimetinib hemifumarate, and imiquimod is also available as imiquimod hydrochloride.

[0124] The present disclosure includes the use of these pharmaceutically acceptable derivatives.

[0125] The present disclosure also includes where appropriate all enantiomers and tautomers of the compounds. The skilled person will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers may be isolated or prepared by methods known in the art.

[0126] Some of the compounds included in the combinations of the present disclosure may exist as stereoisomers and / or geometric isomers - e.g. they may possess one or more asymmetric and / or geometric centres and so may exist in two or more stereoisomeric and / or geometric forms. The present disclosure contemplates the use of all the individual stereoisomers and geometric isomers of those compounds, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).

[0127] The present invention also includes all suitable isotopic variations of the compounds or pharmaceutically acceptable salts thereof. An isotopic variation or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as2H,3H,13C,14C,15N,170,180,31P,32P,35S,18F and36CI, respectively. Certain isotopic variations, for example, those in which a radioactive isotope such as3H or14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0128] The small-molecule antineoplastic agents suitable for use in the combination of the present disclosure, including the pharmaceutically acceptable derivatives thereof, are commercially available and / or can be prepared by synthesis methods known in the art.

[0129] Dabrafenib has the following structure:

[0130] Dabrafenib has the IIIPAC name N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1 ,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene-1 -sulfonamide. Dabrafenib mesylate is sold under the trade name TAFINLAR® and is indicated in Europe as monotherapy or in combination with trametinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection. Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation. In the US, dabrafenib is also indicated for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and with no satisfactory locoregional treatment options. Dabrafenib is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway.

[0131] Encorafenib has the following structure:

[0132] Encorafenib has the IUPAC name methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3- methanesulfonamidophenyl)-1-(propan-2-yl)-1 H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2- yl]carbamate. Encorafenib is sold under the trade name BRAFTOVI® and is indicated incombination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy. Encorafenib is a kinase inhibitor that targets the MAPK pathway.

[0133] Trametinib has the following structure:

[0134] Trametinib has the IIIPAC name N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]- 6,8-dimethyl-2,4,7-trioxo-1 H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide.Trametinib dimethyl sulfoxide is sold under the trade name MEKINST® and is indicated in Europe as monotherapy or in combination with dabrafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection. Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced nonsmall cell lung cancer with a BRAF V600 mutation. In Europe, trametinib is also indicated for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and with no satisfactory locoregional treatment options. Trametinib is an orally bioavailable MEK1 and MEK2 inhibitor.

[0135] Cobimetinib has the following structure:

[0136] Cobimetinib has the IIIPAC name 1-{3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]benzoyl}-3-[(2S)-piperidin-2-yl]azetidin-3-ol. Cobimetinib hemifumarate is sold under the trade name COTELLIC® and is indicated in Europe for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Cobimetinib is also indicated in the US as a single agent for the treatment of adult patients with histiocytic neoplasms. Cobimetinib is a kinase inhibitor targeting MEK.

[0137] Binimetinib has the following structure:

[0138] Binimetinib has the IIIPAC name 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1 H-1 ,3-benzodiazole-6-carboxamide. Binimetinib is sold under the trade name MEKTOVI® and is indicated in combination with encorafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Binimetinib is a kinase inhibitor targeting MEK.

[0139] Imiquimod has the following structure:

[0140] Imiquimod has the IIIPAC name 1-(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4- amine. Imiquimod is sold under various trade names including Aldara®, Bascellex®, Vyloma® and Zyclara®. Imiquimod cream is indicated for the topical treatment of external genital and perianal warts (condylomata acuminata) in adults; small superficial basal cell carcinomas (sBCCs) in adults; and clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AKs) on the face or scalp in immunocompetent adult patients when size or number of lesions limit the efficacy and / or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate. Imiquimod is an immune response modifier that acts by stimulating the innate immune system by activating TLR7.

[0141] Resiquimod has the following structure:

[0142] Resiquimod has the IIIPAC name 1-[4-amino-2-(ethoxymethyl)-1 H-imidazo[4,5- c]quinolin-1-yl]-2-methylpropan-2-ol. Resiquimod is an investigational molecule that has been trialled for e.g. the topical treatment of skin lesions such as those caused by herpes simplex virus (HSV) and cutaneous T-cell lymphoma, as well as an adjuvant to increase the effectiveness of vaccines. The European Commission has granted orphan designation (EU / 3 / 16 / 1653) for resiquimod to be used in the treatment of cutaneous T-cell lymphoma. Resiquimod is an immune response modifier that is an agonist for TLR 7 / 8.

[0143] Motolimod has the following structure:

[0144] Motolimod has the IIIPAC name 2-amino-N,N-dipropyl-8-[4-(pyrrolidine-1- carbonyl)phenyl]-3H-1-benzazepine-4-carboxamide. Motolimod is an investigational molecule that has been trialled for use as an adjuvant therapy against various cancers. Motolimod is an immune response modifier that is a TLR8 agonist.

[0145] Temuterkib has the following structure:

[0146] Temuterkib has the IIIPAC name 6,6-dimethyl-2-[2-[(2-methylpyrazol-3- yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one. Temuterkib is an investigational ERK1 / 2 inhibitor being trialled e.g. for the treatment of a variety of cancers.

[0147] Adagrasib has the following structure:

[0148] Adagrasib has the IIIPAC name 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2- enoyl)piperazin-2-yl]acetonitrile. Adagrasib is sold under the trade name KRAZATI® and is indicated in the US for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.

[0149] Sotorasib has the following structure:

[0150] Sotorasib has the IUPAC name 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4- methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3- d]pyrimidin-2(1H)-one. Sotorasib is sold under the trade names LUMAKRAS® and LUMYKRAS® and is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.Antineoplastic antibody

[0151] In various aspects and embodiments, the present disclosure provides compositions comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; for example, as the first composition in the combination disclosed herein.

[0152] As used herein, the term “antibody” includes means an immunoglobulin molecule (or a group of immunoglobulin molecules) that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the terms "antibody" and "antibodies" are terms of art and can be used interchangeably herein and refer to a molecule with an antigen-binding site that specifically binds an antigen.

[0153] Antibodies can include, for example, monoclonal antibodies, recombinantly produced antibodies, human antibodies, humanized antibodies, resurfaced antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain- antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), affybodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti- Id) antibodies (including, e.g., anti-anti-ld antibodies), bispecific antibodies, and multi-specific antibodies. In certain embodiments, antibodies described herein refer to polyclonal antibody populations. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgGi, lgG2, IgGs, lgG4, IgAi, or lgA2), or any subclasses (isotypes) thereof (e.g. lgG1 , lgG2, lgG3, lgG-4, lgA1 and lgA2), of immunoglobulin molecule, based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated or fused to other molecules such as toxins, radioisotopes, other polypeptides etc.

[0154] As used herein, the terms "variable region" or "variable domain" are used interchangeably and are common in the art. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR).

[0155] There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991 , National Institutes of Health, Bethesda Md.), "Kabat"); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al, J. Molec. Biol. 273:927-948 (1997)). In addition, combinations of these two approaches are sometimes used in the art to determine CDRs. It is understood that the identification of CDRs in a variable region also identifies the FRs as the sequences flanking the CDRs.

[0156] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. (5th Ed., 1991 , National Institutes of Health, Bethesda, Md.) ("Kabat").

[0157] The amino acid position numbering as in Kabat, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al. (Sequences of Immunological Interest. (5th Ed., 1991 , National Institutes of Health, Bethesda, Md.), "Kabat"). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain can include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues can be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard" Kabat numbered sequence. Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.Loop Kabat AbM ChothiaLI L24-L34 L24-L34 L24-L34L2 L50-L56 L50-L56 L50-L56L3 L89-L97 L89-L97 L89-L97Hl H31-H35B H26-H35B H26-H32..34(Kabat Numbering)Hl H31-H35 H26-H35 H26-H32(Chothia Numbering)H2 H50-H65 H50-H58 H52-H56H3 H95-H102 H95-H102 H95-H102

[0158] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

[0159] The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

[0160] The terms "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or sub-sequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art that can be used to obtain alignments of amino acid or nucleotide sequences. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al, Proc. Natl. Acad. Sci., 87:2264-2268 (1990), as modified in Karlin et al., Proc. Natl. Acad. Sci., 90:5873-5877 (1993), and incorporated into the NBLAST and XBLAST programs (Altschul et al., Nucleic Acids Res., 25:3389-3402 (1991)). In certain embodiments, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997). BLAST-2, WU-BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)), ALIGN, ALIGN-2 (Genentech, South San Francisco, California) or Megalign (DNASTAR) are additional publicly available software programs that can be used to align sequences. In certain embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in GCG software (e.g., using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 90 and a length weight of 1 , 2, 3, 4, 5, or 6). In certain alternative embodiments, the GAP program in the GCG softwarepackage, which incorporates the algorithm of Needleman and Wunsch (J. Mol. Biol. (48):444- 453 (1970)) can be used to determine the percent identity between two amino acid sequences (e.g., using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1 , 2, 3, 4, 5). Alternatively, in certain embodiments, the percent identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, the percent identity can be determined using the ALIGN program (version 2.0) and using a PAM120 with residue table, a gap length penalty of 12 and a gap penalty of 4. Appropriate parameters for maximal alignment by particular alignment software can be determined by one skilled in the art. In certain embodiments, the default parameters of the alignment software are used. In certain embodiments, the percentage identity "X" of a first amino acid sequence to a second sequence amino acid is calculated as 100 x (Y / Z), where Y is the number of amino acid residues scored as identical matches in the alignment of the first and second sequences (as aligned by visual inspection or a particular sequence alignment program) and Z is the total number of residues in the second sequence. If the length of a first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be longer than the percent identity of the second sequence to the first sequence.

[0161] As a non-limiting example, whether any particular polynucleotide has a certain percentage sequence identity (e.g., is at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% identical) to a reference sequence can, in certain embodiments, be determined using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wl 53711). Bestfit uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics 2: 482 489 (1981)) to find the best segment of homology between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for instance, 95% identical to a reference sequence described herein, the parameters are set such that the percentage of identity is calculated over the full length of the reference nucleotide sequence and that gaps in homology of up to 5% of the total number of nucleotides in the reference sequence are allowed.

[0162] The term "antibody fragment" refers to a portion of an intact antibody. An "antigenbinding fragment" refers to a portion of an intact antibody that binds to an antigen. An antigenbinding fragment can contain the antigenic determining variable regions of an intact antibody.Examples of antibody fragments include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies.

[0163] A "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, "monoclonal" antibody or antigen-binding fragment thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0164] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g. murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g. murine) that have the desired specificity, affinity, and capability ("CDR grafted") (Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988)). In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody or fragment from a non-human species (e.g., murine) that has the desired specificity, affinity, and capability. The humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody or antigen-binding fragment thereof specificity, affinity, and / or capability. In general, the humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples ofmethods used to generate humanized antibodies are described in U.S. Pat. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91 (3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996). In some embodiments, a "humanized antibody" is a resurfaced antibody.

[0165] The term "chimeric" antibodies or antigen-binding fragments thereof refers to antibodies or antigen-binding fragments thereof wherein the amino acid sequence is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies or antigen-binding fragments thereof derived from one species of mammals (e.g., mouse) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies or antigen-binding fragments thereof derived from another (usually human) to avoid eliciting an immune response in that species.

[0166] As used herein, the terms "immunospecifically binds," "immunospecifically recognizes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen can bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIAcore®, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, molecules that immunospecifically bind to an antigen bind to the antigen with a Kd that is at least 2 logs, 2.5 logs, 3 logs, or 4 logs lower than the Kd when the molecules bind non-specifically to another antigen.

[0167] In preferred embodiments, the antineoplastic antibody or antigen-binding fragment thereof is a monoclonal antibody or an antigen-binding fragment thereof.

[0168] The antineoplastic antibody may, in various embodiments, be a chimeric, humanised or human antibody, or an antigen-binding fragment thereof. Preferably, the antineoplastic antibody is a humanised or human antibody or antigen-binding fragment thereof. For instance, the antineoplastic antibody is more preferably a humanised or human monoclonal antibody, or an antigen-binding fragment thereof.

[0169] In various embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof binds to a tumor antigen. As used herein, the term “tumor antigen” includes tumor-specific antigens (i.e. antigens expressed by tumor cells that are not present in normalhost cells) as well as tumor-associated antigens (i.e. self-antigens expressed by tumor cells that are present in a subset of normal host cells). Tumor-associated antigens are often differentially expressed or overexpressed by tumor cells relative to normal host cells, allowing for preferential recognition of tumor cells.

[0170] In various embodiments, the antineoplastic antibody or antigen-binding fragment thereof, e.g. a human or humanised monoclonal antibody or antigen-binding fragment thereof, specifically binds the tumor antigen. In various embodiments, the antineoplastic antibody or antigen-binding fragment thereof, preferably a human or humanised monoclonal antineoplastic antibody or antigen-binding fragment thereof, specifically binds to a tumor-specific antigen. In other embodiments, the antineoplastic antibody or antigen-binding fragment thereof, preferably a human or humanised monoclonal antineoplastic antibody or antigen-binding fragment thereof, specifically binds to a tumor-associated antigen.

[0171] In various embodiments of the present disclosure, the antineoplastic antibody or antigen-binding fragment thereof is an anti-tyrosinase-related 1 (TYRP1) antibody or antigenbinding fragment thereof. Without wishing to be bound by theory, TYRP1 is a melanocytespecific gene product involved in melanin synthesis. The TYRP1 gene is also believed to have a non-coding function that indirectly promotes melanoma tumor cell proliferation, especially when highly expressed in cells.

[0172] In various embodiments, the antineoplastic antibody or antigen-binding fragment thereof comprises or is flanvotumab, TA99, or an antigen-binding fragment thereof. Preferably, the antineoplastic antibody or antigen-binding fragment thereof is flanvotumab or an antigenbinding fragment thereof, more preferably flanvotumab.

[0173] In various embodiments of the present disclosure, the antineoplastic antibody or antigen-binding fragment thereof is an anti-VEGF (Vascular Endothelial Growth Factor) antibody or antigen-binding fragment thereof. For example, in various embodiments, the antineoplastic antibody or antigen-binding fragment thereof comprises or is bevacizumab or an antigen-binding fragment thereof, preferably bevacizumab. Bevacizumab is sold under the trade name AVASTIN® and is indicated in combination with various antineoplastic agents for the treatment of various cancers.

[0174] In various embodiments of the present disclosure, the antineoplastic antibody or antigen-binding fragment thereof is an anti-HER2 (human epidermal growth factor receptor 2 / receptor tyrosine-protein kinase erbB-2) antibody or antigen-binding fragment thereof. Forexample, in various embodiments, the antineoplastic antibody or antigen-binding fragment thereof comprises or is trastuzumab or an antigen-binding fragment thereof, preferably trastuzumab. Trastuzumab is sold under the trade name HERCEPTIN® and is indicated for the treatment of breast cancers as a monotherapy and in combination with radiation and / or further antineoplastic agents.

[0175] In other embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof comprises at least one immunomodulatory antibody or antigen-binding fragment thereof. As used herein, “immunomodulatory antibodies” refer to antibodies that modify the human body’s immune response. For example, immunomodulatory antibodies may bind to receptors on immune cells rather than tumour cells and thereby alter the signals that are transmitted into the immune cells to make them more active and better at killing cancer cells. Immunomodulatory antibodies include checkpoint inhibitors as well as antibodies binding molecules such as interleukins, chemokines and their respective receptors.

[0176] In preferred embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof comprises at least one immune checkpoint inhibitor. In various embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof is an immune checkpoint inhibitor.

[0177] The term “immune checkpoint inhibitor” is a term in the art. Without wishing to be bound by theory, immune checkpoints are a normal part of the immune system, where they prevent an immune response from being so strong that it destroys healthy cells in the body. Immune checkpoints engage when proteins on the surface of immune cells called T cells recognize and bind to partner proteins on other cells, such as some tumor cells. These proteins are called immune checkpoint proteins. When the checkpoint and partner proteins bind together, they send an “off” signal to the T cells. This can prevent the immune system from destroying the cancer. Thus, the immune checkpoint inhibitors act by inhibiting an immune checkpoint protein involved in the interaction between T cells and other cells e.g. host and tumor cells. For example, immune checkpoint inhibitors may inhibit PD-1 (programmed cell death protein 1) or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), or ligands thereof. For example, POLI (programmed death ligand 1) is a ligand of PD-1.

[0178] Thus, in various embodiments the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof that bind programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and / or ligands thereof.

[0179] In preferred embodiments, the immune checkpoint inhibitor is an anti-PD-1 or anti-PD- L1 antibody or antigen-binding fragment thereof. Such immune checkpoint inhibitors are known in the art and commercially available and the skilled person will be able to identify such inhibitors based on their common general knowledge.

[0180] For example, in various embodiments the anti-PD-1 or anti-PD-L1 antibody may be selected from nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, and sintilimab. Preferably, the anti-PD-1 or anti-PD-L1 antibody may be selected from nivolumab and pembrolizumab. Antigen-binding fragments of the foregoing are also contemplated.

[0181] Nivolumab is a fully human monoclonal antibody against PD-1 sold under the trade name OPDIVO®. Nivolumab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g. https: / / www.ema.europa.eu / en / documents / product-information / opdivo-epar-product- information en.pdf).

[0182] Pembrolizumab is a humanized antibody against PD-1 sold under the trade name KEYTRUDA®. Pembrolizumab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g. https: / / www.ema.europa.eu / en / documents / product-information / keytruda-epar-product- information en.pdf).

[0183] Atezolizumab is a fully humanized, monoclonal antibody against PD-L1 sold under the trade name TECENTRIQ®. Atezolizumab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g. https: / / www.ema.europa.eu / en / documents / product-information / tecentriq-epar-product- information en.pdf).

[0184] Cemiplimab is a fully human monoclonal antibody against PD-1 sold under the trade name LIBTAYO®. Cemiplimab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g. https: / / www.ema.europa.eu / en / documents / product-information / libtayo-epar-product- information en.pdf).

[0185] Avelumab is a human monoclonal antibody against PD-L1 and is sold under the trade name BAVENCIO®. Avelumab is indicated in Europe and the US for the treatment of variouscancers as monotherapy or in combination therapies (see e.g.

[0186] Durvalumab is a fully human monoclonal antibody against PD-L1 sold under the trade name IMFINZI®. Durvalumab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g.

[0187] Tislelizumab is a humanized monoclonal antibody against PD-1 sold under the trade name TEVIMBRA®. Tislelizumab is currently indicated in Europe for the treatment of oesophageal squamous cell carcinoma as monotherapy (see

[0188] Sintilimab is a fully human monoclonal antibody against PD-1 sold under the trade name TYVYT®. Sintilimab has been approved in China and is currently in numerous trials for the treatment of solid tumors as monotherapy or in combination.

[0189] In preferred embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody or antigen-binding fragment thereof. In further embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof is selected from ipilimumab and antigen-binding fragments thereof.

[0190] Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody sold under the trade name YERVOY®. Ipilimumab is indicated in Europe and the US for the treatment of various cancers as monotherapy or in combination therapies (see e.g.

[0191] In various embodiments of the present disclosure, the immune checkpoint inhibitor is an anti-LAG3 (Lymphocyte-activation gene 3) antibody or antigen-binding fragment thereof. Thus, in various embodiments the anti-LAG3 antibody is selected from relatlimab and fianlimab. Antigen-binding fragments thereof are also contemplated.

[0192] In various embodiments of the present disclosure, the immune checkpoint inhibitor is an anti-TIGIT (T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains) antibody or antigen-binding fragment thereof. Thus, in various embodiments the anti-TIGIT antibody is selected from tiragolumab and vibostolimab. Antigenbinding fragments thereof are also contemplated.

[0193] Other exemplary checkpoint proteins that may be targeted by antineoplastic antibodies or antigen-binding fragments thereof according to the present disclosure include, but are not limited to, CD40, CD73, and CD39.

[0194] In some embodiments, the antineoplastic antibody may consist of an immune check point inhibitor according to any of the embodiments disclosed herein above. For example, an anti-PD-1 , anti-PD-L1 , or anti-CTLA-4 antibody or antigen-binding fragment thereof may be the sole antineoplastic antibody in the first composition of the combination disclosed herein.

[0195] As already indicated, immune checkpoint inhibitors are often indicated for use in combination therapies such as those disclosed herein. Thus, in other embodiments, a first antineoplastic antibody as disclosed herein above may be used in combination with a second antineoplastic antibody or antigen-binding fragment thereof, preferably wherein the first antineoplastic antibody or antigen-binding fragment thereof and the second antineoplastic antibody or antigen-binding fragment thereof are different.

[0196] Thus, in various embodiments an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-CTLA-4 antibody or antigen binding fragment thereof. For example, nivolumab may be used in combination with ipilimumab.

[0197] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-LAG3 antibody or antigen-binding fragment thereof. For example, nivolumab may be used in combination with relatlimab, said combination being sold under the trade name OPDUALAG® for the treatment of advanced melanoma. In another exemplary embodiment, fianlimab may be used in combination cemiplimab.

[0198] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-VEGF antibody or antigen-binding fragment thereof. For example, atezolizumab may be used in combination with bevacizumab.

[0199] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-TIGIT antibody or antigen-binding fragment thereof. For example, atezolizumab may be used in combination with tiragolumab. In further exemplary embodiments, vibostolimab may be used in combination with pembrolizumab.

[0200] Such embodiments are further defined herein in connection with the combination of the present disclosure.

[0201] The first antineoplastic antibody or antigen-binding fragment thereof and the second antineoplastic antibody or antigen-binding fragment thereof are typically comprised in different compositions, for example in a combination for simultaneous, separate or sequential administration as further described herein below.

[0202] In various embodiments, the antineoplastic antibody is isolated or purified.

[0203] Generally, an isolated antibody is one that is substantially free of other antibodies with different antigenic specificities than the isolated antibody. For example, in a particular embodiment, a preparation of an antibody described herein is substantially free of cellular material and / or chemical precursors. The language "substantially free of cellular material" includes preparations of an antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein") and / or variants of an antibody, for example, different post-translational modified forms of an antibody. When the antibody described herein is recombinantly produced, it is also generally substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, 2%, 1%, 0.5%, or 0.1% of the volume of the protein preparation. When the antibody described herein is produced by chemical synthesis, it is generally substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody described herein have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.

[0204] Thus, in various embodiments the antineoplastic antibody or antigen-binding fragment thereof may be an isolated or purified anti-TYRP1 antibody or antigen-binding fragment thereof, which preferably may be a human or humanised monoclonal antibody or antigenbinding fragment thereof. In other embodiments, the antineoplastic antibody or antigen-binding fragment thereof may be an isolated or purified antibody that binds PD-1 , CTLA-4, or ligands thereof; any of which may preferably be human or humanised monoclonal antibodies or antigen-binding fragments thereof.

[0205] In the various aspects of the present disclosure, the at least one polyether-polyester copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8.

[0206] Compositions as defined herein comprising said polyether-polyester copolymer may be liquid at room temperature. For example, in preferred embodiments the compositions may be liquid at room temperature and form a semi-solid or solid implant when injected into an aqueous environment. Compositions according to the present disclosure may, for example, be liquid at room temperature and form a semi-solid or solid implant when administered by subcutaneous, peri-turmoral or intra-tumoral injection.

[0207] The compositions described above comprising at least one polyether-polyester copolymer as defined herein are typically suitable for forming a depot when injected into the body, i.e. an “in situ depot”.

[0208] Such compositions may be administered via depot injection. The term “depot injection” is an injection of a flowing pharmaceutical composition deposits a drug in a localized mass, such as a solid or semi-solid mass, called a “depot”. The depots as defined herein are in situ forming upon injection. Thus, the formulations can be prepared as solutions or suspensions and can be injected into the body.

[0209] An “in situ depot” is a solid or semi-solid, localized mass formed by precipitation of the pharmaceutical composition after injection of the composition into the subject. The pharmaceutical composition comprises copolymers which are substantially insoluble in aqueous solution. Thus, when the pharmaceutical composition contacts the aqueous environment of the human or animal body, a phase inversion occurs causing the composition to change from a liquid to a solid, i.e. precipitation of the composition occurs, leading to formation of an “in situ depot”.

[0210] An “in situ depot” can be clearly distinguished from hydrogel pharmaceutical formulations described in the prior art. Hydrogels have three-dimensional networks that are able to absorb large quantities of water. The polymers making up hydrogels are soluble inaqueous solution. By contrast, the polymers used in the present invention are substantially insoluble in aqueous solution. The compositions of the invention typically contain low concentrations of water, or water is absent. For example, the pharmaceutical compositions of the invention may comprise less than 0.5% (w / w) water or may be substantially free of water.

[0211] In preferred embodiments the at least one polyether-polyester copolymer (c) is selected from: i. a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and ii. a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and iii. a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; iv. or any combination thereof.

[0212] As mentioned above, B represents a polyether and comprises or is polyethylene glycol (PEG) or end-capped PEG. For the multi-arm copolymer i) this typically means that B is a multiarm polyether obtainable from the reaction of PEG with a polyol, or more typically the reaction of the precursor of PEG which is ethylene oxide with a polyol. When the polyether-polyester copolymer is a triblock copolymer, B is PEG. When the polyether-polyester copolymer is a diblock copolymer, B is an end-capped PEG such as methoxy-PEG.

[0213] The copolymers used in the present disclosure can be described as “bioresorbable” or “biodegradeable” which means that the block copolymers undergo hydrolysis in vivo to form their constituent (m)PEG and oligomers or monomers or repeat units derived from thepolyester block. For example, poly(s-caprolactone-co-lactic acid) (PCLA) undergoes hydrolysis to form 6-hydroxycaproic acid (6-hydroxyhexanoic acid) and lactic acid. The result of the hydrolysis process leads to a progressive mass loss of the depot and ultimately to its disappearance.

[0214] The molecular weight of each copolymer is the number average molecular weight. The number average molecular weight is typically measured using gel permeation chromatography (GPC) using a calibration curve obtained from polystyrene standards.

[0215] In a preferred embodiment of the present disclosure, the polyether of the polyetherpolyester copolymer comprises poly(ethylene glycol) (PEG) or is PEG, or end-capped PEG such as methoxy-PEG.

[0216] In preferred embodiments, the polyester of the polyether-polyester copolymer comprises lactoyl repeat units. A person skilled in the art will understand the term “lactoyl” in the context of repeat units to be interchangeable with the term “lactic” repeat units.

[0217] In one embodiment, the polyester of the polyether-polyester copolymer is poly(D,L- lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA), or poly(s-caprolactone-co-lactic acid) (PCLA), preferably poly(D,L-lactic acid). The polyesters are terminated by a hydroxyl (- OH) end group. The polymers according to the present disclosure preferably have an acid number below 15 or preferably below 5. Acid number is the measure of the amount of free acids in a substance usually expressed as the number of milligrams of potassium hydroxide (KOH) required to neutralize one gram of the substance.

[0218] The PEG-PLA copolymer comprises PEG and PLA blocks and may be obtainable by reacting PEG with D,L-lactide, preferably by ring-opening polymerisation of the D,L-lactide initiated by the PEG. The polyether- PLGA copolymer is obtainable by reacting PEG with D,L- lactide and glycolide, preferably by ring-opening polymerisation of the D,L-lactide and the glycolide initiated by the PEG. The polyether-PCLA copolymer is obtainable by reacting PEG with s-caprolactone and D,L-lactide, preferably by ring opening of s-caprolactone and D,L- lactide initiated by the PEG. Preferably the polyether-polyester copolymer is a PEG-PLA copolymer.

[0219] The end-capped polyethylene glycol of the diblock copolymer is preferably methoxypolyethylene glycol.

[0220] In one embodiment the polyether-polyester copolymer is a multi-arm copolymer. The term “multi-arm copolymer” means a polymer with at least three polyester arms attached to a central core, the central core of the invention comprising a polyether. The polyester arms may be referred to as “branches”, “arms” or “chains”. The term “multi-arm copolymer” has the same meaning as the term “star copolymer” or “star-shaped copolymer” or “multi-branched copolymer” and these terms are used interchangeably throughout.

[0221] In one embodiment the polyether-polyester copolymer is a multi-arm copolymer wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units.

[0222] In various embodiments the polyether-polyester copolymer is a multi-arm copolymer having a molar ratio of the ester repeat unit to the ethylene oxide repeat unit of from 0.5 to 25, preferably from 1 to 10, more preferably from 2 to 6.

[0223] In a preferred embodiment the polyether-polyester copolymer is a multi-arm copolymer having from 3 to 8 arms.

[0224] If the polyether-polyester copolymer is a multi-arm copolymer, the central core is a multi-arm polyether which may be obtainable from poly(ethylene glycol) (PEG) and a polyol. The multi-arm polyether may be formed by reaction of ethylene oxide with a polyol. The multiarm polyether is obtainable by reaction of ethylene oxide with a polyol.

[0225] A polyol is an organic compound comprising a plurality of hydroxyl groups. Preferably, the polyol comprises at least three hydroxyl groups, optionally wherein the polyol is a hydrocarbon substituted with at least three hydroxyl groups, optionally 3 to 8 hydroxyl groups, for example 3, 4, 5, 6 or 8 hydroxyl groups. In various embodiments, the polyol is pentaerythritol (PE), dipentaerythritol, trimethylolpropane (TMP), glycerol, erythritol, xylitol, di(trimethylolpropane (diTMP) sorbitol, or inositol.

[0226] In one embodiment the polyol further comprises one or more ether groups.

[0227] Examples of multi-arm polyethers are presented in Formulae 1 to 4:wherein Ri, H or alkyl, x is 0 or 1 and m is an integer between 2 and 76Formula 1wherein m is an integer between 5 and 40Formula 2wherein m is an integer between 5 and 40Formula 3wherein m is an integer between 25 and 30 and v is 6Formula 4

[0228] In various embodiments of the multi-arm copolymer, the number of arms is 4, the molecular weight of the PEG core is 2 kDa, and the lactic acid / ethylene oxide molar ratio is 3 or 6.

[0229] Preferably the polyether-polyester copolymer has the formula B(A)nwherein B represents the polyether comprising PEG and A represents the polyester arms and n is an integer which is 1 , 2, 3, 4, 5, 6, 7 or 8. When n is i , the copolymer is a diblock, when n is 2, the copolymer is a triblock and when n is 3 or more, the copolymer is a multi-arm copolymer.

[0230] In the case of a diblock, the copolymer is linear and consists of a polyether and a polyester (A-B) such as mPEG-PLA; m representing an end-capping group such as methoxy.

[0231] In the case of a triblock the copolymer is linear and consists of a central polyether flanked by polyesters (A-B-A), such as PLA-PEG-PLA.

[0232] The molecular weight of the PEG chain, also referred to as the PEG repeat unit, namely - (CH2CH2O)n- where n is an integer, is measured using gel permeation chromatography (GPC) using a calibration curve obtained from polystyrene standards. The molecular weight measured is the number average molecular weight (Mn).

[0233] General formulae for the diblock and triblock copolymers are set out below:Diblock Copolymers (DB)Triblock Copolymers (TB)

[0234] In a preferred embodiment the polyether-polyester copolymer is a mixture of a diblock copolymer and a triblock copolymer. In one embodiment the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the diblock copolymer is from 0.8 to 15, preferably from 1 to 10, most preferably 1 to 4. In one embodiment the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the triblock copolymer is from 0.5 to 22, preferably from 0.5 to 10, most preferably from 1 to 6.

[0235] In some embodiments, for the triblock and / or the diblock copolymer the molecular weight of the PEG repeat unit is from 0.35 to 2 kDa and the lactic acid / ethylene molar ratio is from 2 to 6.

[0236] In some embodiments, for the triblock copolymer the molecular weight of the PEG repeat unit is from 1 to 2 kDa and the lactic acid / ethylene ratio is 2 to 6 and for the diblock copolymer the molecular weight of the mPEG is from 1 to 2 kDa and the lactic acid / ethylene oxide ratio is from 2 to 4.

[0237] In some embodiments, for the triblock copolymer the molecular weight of the PEG repeat unit is 1 kDa, and the lactic acid / ethylene oxide molar ratio is 4 or 6 and for the diblock copolymer the molecular weight of the PEG repeat unit is 2 kDa, and the lactic acid / ethylene oxide molar ratio is 2.4 or 3.

[0238] In some embodiments, for the triblock copolymer the molecular weight of the PEG is 1 kDa, and the lactic acid / ethylene oxide molar ratio is 6 and for the diblock copolymer the molecular weight of the mPEG is 1 kDa, and the lactic acid / ethylene oxide molar ratio is 4.

[0239] In some embodiments, for the triblock copolymer the molecular weight of the PEG is 1 kDa, and the lactic acid / ethylene oxide molar ratio is 6 and for the diblock copolymer the molecular weight of the mPEG is 2 kDa, and the lactic acid / ethylene oxide molar ratio is 2.4.

[0240] In some embodiments, for the triblock copolymer the molecular weight of the PEG is 2 kDa, and the lactic acid / ethylene oxide molar ratio is 2 and for the diblock copolymer the molecular weight of the mPEG is 2 kDa, and the lactic acid / ethylene oxide molar ratio is 2.4 or 3.

[0241] In further preferred embodiments:- when the copolymer is a multi-arm copolymer B(A)n, each polyether arm is composed of 2 to 150 ethylene oxide repeat units and each polyester arm A is composed of 4 to 200 ester repeat units, with a preferred molar ratio of the ester repeat unit to the ethylene oxide repeat unit in the multi-arm copolymer ranging from 1 to 10 and more preferably 2 to 6; when the copolymer is a triblock copolymer A-B-A, B is composed of 3 to 300 ethylene oxide repeat units and each A arm is composed of 1 to 3,000 ester repeat units, with a preferred molar ratio of the ester repeat unit to the ethylene oxide repeat unit in the triblock copolymer ranging from 0.5 to 22, preferably 0.5 to 10 and more preferably 1 to 6; and- when the copolymer is a diblock copolymer A-B, B is composed of 2 to 250 ethylene oxide repeat units and A is composed of 1 to 3,000 ester repeat units, with a preferred molar ratio of the ester repeat unit to the ethylene oxide repeat unit in the diblock copolymer ranging from 0.8 to 15, preferably 1 to 10 and more preferably 1 to 4.

[0242] More details on the copolymers used in the present invention can be found in WG2012 / 090070A1 , WO2019016233A1 , WO2019016234A1 , WO2019016236A1 and WO2020 / 144239A1 , each of which are incorporated by reference herein.

[0243] The triblock PLA-PEG-PLA polymers described herein are labelled PxRy, where x represent the size of the PEG chain in kDa (number average molecular weight) and y is the LA / EO molar ratio. The diblock mPEG-PLA polymers described herein are labelled dPxRy where x represents the size of the PEG chain in kDa (number average molecular weight) and y is the LA / EO molar ratio. The star-shaped sPEG-PLA polymers described herein are labelled szPxRy where x represents the size of the PEG central core in kDa (number average molecular weight), y is the LA / EO molar ratio and z the arm number.Compositions(a) Antibody-containing compositions

[0244] As described herein, aspects of the present disclosure provide a combination comprising a first composition and a second composition as defined herein. The first composition comprises at least one antineoplastic antibody or an antigen-binding fragment thereof.

[0245] The at least one antineoplastic antibody or antigen-binding fragment thereof of any of the compositions defined herein above may be an antineoplastic antibody or antigen-binding fragment thereof as defined in any of the embodiments disclosed herein.

[0246] Thus in various embodiments the present disclosure provides a composition comprising at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised.

[0247] In any of the preceding embodiments, the at least one antineoplastic antibody or an antigen-binding fragment thereof may bind to a tumor antigen, e.g. a tumor-specific or tumor- associated antigen. Thus, in preferred embodiments the composition defined herein above comprises (i) at least one monoclonal antibody or an antigen-binding fragment thereof that binds a tumor antigen, e.g. a tumor-specific or tumor-associated antigen. In preferred embodiments, the antibody or antigen-binding fragment thereof specifically binds the tumor antigen.

[0248] In further embodiments, the composition defined herein above comprises (i) at least one monoclonal antibody or an antigen-binding fragment thereof that binds TYRP1. Preferably, the antibody or antigen-binding fragment thereof is a human or humanised antibody or antigenbinding fragment thereof. In preferred embodiments, the antibody or antigen-binding fragment thereof specifically binds TYRP1. For example, the antibody or antigen-binding fragment thereof may be selected from TA99, flanvotumab, and antigen-binding fragments thereof. Preferably, the antibody may be flanvotumab.

[0249] In other embodiments, the composition may comprise an antibody or antigen-binding fragment thereof that binds VEGF or HER2, for example bevacizumab or trastuzumab.

[0250] In other embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof comprises at least one immune checkpoint inhibitor, preferably an anti-PD-1 , anti-PD-L1 , and / or an anti-CTLA-4 antibody, or antigen-binding fragment thereof. The anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be selected from nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab, and antigen-binding fragments thereof. The anti-CTLA-4 antibody or antigen-binding fragment thereof may be selected from ipilimumab and antigen-binding fragments thereof. In further embodiments, the immune checkpoint inhibitor may be an anti-LAG-3 antibody or antigenbinding fragment thereof, for example relatlimab or fianlimab. In yet further embodiments, the immune checkpoint inhibitor may be an anti-TIGIT antibody or antigen-binding fragment thereof, for example tiragolumab or vibostolimab. Other immune checkpoint inhibitors include antibodies or antigen-binding fragments thereof that bind CD73, CD39, CD40, interleukins and / or chemokines.

[0251] In further embodiments, a first antineoplastic antibody or antigen-binding fragment thereof may be used in combination with a second antineoplastic antibody or antigen-binding fragment thereof, wherein said first antineoplastic antibody or antigen-binding fragment thereof and second antineoplastic antibody or antigen-binding fragment thereof are preferably different. For example, the first antineoplastic antibody or antigen-binding fragment thereof may be an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof and the second antineoplastic antibody or antigen-binding fragment thereof may be an anti-CTLA-4 antibody or antigen-binding fragment thereof. In preferred embodiments, the first antibody may be nivolumab and the second antibody may be ipilimumab.

[0252] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-LAG3 antibody or antigen-binding fragment thereof. For example, nivolumab may be used in combination with relatlimab. In another exemplary embodiment, fianlimab may be used in combination cemiplimab.

[0253] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-VEGF antibody or antigen-binding fragment thereof. For example, atezolizumab may be used in combination with bevacizumab.

[0254] In other embodiments, an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be used in combination with an anti-TIGIT antibody or antigen-binding fragment thereof. For example, atezolizumab may be used in combination with tiragolumab. In further exemplary embodiments, vibostolimab may be used in combination with pembrolizumab.

[0255] In various embodiments, the first composition may comprise at least one polyetherpolyester copolymer, wherein the copolymer has the formula:B(A)n wherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.

[0256] Thus, a further aspect of the present disclosure provides a pharmaceutical composition comprising:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0257] Similarly, the at least one polyether-polyester copolymer of any of the foregoing compositions may be as defined in any of the embodiments described herein.

[0258] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0259] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula: Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(ii) an organic solvent.

[0260] In any of the preceding embodiments, the at least one antineoplastic antibody or an antigen-binding fragment thereof may bind to a tumor antigen, e.g. a tumor-specific or tumor- associated antigen. Thus, in preferred embodiments the composition defined herein above comprises (i) at least one monoclonal antibody or an antigen-binding fragment thereof that binds a tumor antigen, e.g. a tumor-specific or tumor-associated antigen. In preferred embodiments, the antibody or antigen-binding fragment thereof specifically binds the tumor antigen.

[0261] In further embodiments, the composition defined herein above comprises (i) at least one monoclonal antibody or an antigen-binding fragment thereof that binds TYRP1. Preferably, the antibody or antigen-binding fragment thereof is a human or humanised antibody or antigenbinding fragment thereof. In preferred embodiments, the antibody or antigen-binding fragment thereof specifically binds TYRP1.

[0262] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that binds TYRP1 , preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0263] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that binds TYRP1 , preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0264] In particularly preferred embodiments the at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof is flanvotumab or an antigen-binding fragment thereof, more preferably flanvotumab.

[0265] In other embodiments, the at least one antineoplastic antibody or antigen-binding fragment thereof comprises at least one immune checkpoint inhibitor, preferably an anti-PD-1 , anti-PD-L1 , and / or an anti-CTLA-4 antibody, or antigen-binding fragment thereof.

[0266] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0267] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0268] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0269] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0270] In the foregoing embodiments, the anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof may be selected from nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab, and antigen-binding fragments thereof.

[0271] In the foregoing embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof may be selected from ipilimumab and antigen-binding fragments thereof.

[0272] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0273] In any of the foregoing compositions the at least one polyether-polyester copolymer is present in the pharmaceutical composition in an amount of from about 10 to about 75 wt% based on the composition, preferably about 10 to about 40 wt% based on the composition, more preferably from about 10 to about 30 wt% based on the composition.

[0274] In any of the foregoing compositions when the at least one polyether-polyester is a mixture of a triblock copolymer and a diblock copolymer, each of the copolymer is present in an amount of from 5 to 25 wt% based on the composition, preferably from about 10 to 20% based on the composition.

[0275] Thus, in various embodiments the pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer in an amount of from about 10 to about 40 wt% based on the composition, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0276] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0277] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;wherein the mixture is present in an amount of from about 10 to about 40 wt%, based on the composition and(iii) an organic solvent.

[0278] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0279] In preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0280] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;wherein the mixture is present in an amount of from about 10 to about 40 wt%, based on the composition; and(iii) an organic solvent.

[0281] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0282] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0283] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;wherein the mixture is present in an amount of from about 10 to about 40 wt% based on the composition; and(iii) an organic solvent.

[0284] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0285] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0286] In any of the foregoing compositions, the organic solvent may be present in the composition in an amount of from about 15 to about 85 wt%, preferably from about 40 to about 75 wt%, more preferably from about 50 to about 85 wt%, based on the composition.

[0287] Thus, in various embodiments the pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0288] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0289] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0290] In preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0291] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0292] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0293] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt%, based on the composition.

[0294] In various embodiments the pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0295] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0296] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0297] In preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0298] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0299] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0300] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 40 to about 75 wt%, based on the composition.

[0301] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0302] In various embodiments the pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer in an amount of from about 10 to about 40 wt% based on the composition, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0303] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0304] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt%, based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0305] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0306] In preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyetherarm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0307] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt%, based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0308] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0309] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a centralcore which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0310] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof, preferably wherein said antibody or antigenbinding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0311] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0312] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0313] In various embodiments, the antineoplastic antibody or antigen-binding fragment thereof is present in the composition in an amount of from about 0.2 to about 20 wt%, preferably from about 0.2 to about 10 wt%, based on the first composition.

[0314] Thus, in various embodiments the pharmaceutical composition comprises:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof in an amount of from about 0.2 to about 20 wt% based on the composition;(ii) at least one polyether-polyester copolymer in an amount of from about 10 to about 40 wt% based on the composition, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0315] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0316] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0317] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0318] In preferred embodiments, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0319] In another embodiment, the pharmaceutical composition comprises:(i) at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof that is an immune checkpoint inhibitor in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0320] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0321] In further preferred embodiments, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a multi-arm copolymer in an amount of from about 10 to about 40 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0322] In another preferred embodiment, the pharmaceutical composition comprises:(i) at least one anti-PD-1 , anti-PD-L1 or anti-CTLA4 monoclonal antibody or an antigen-binding fragment thereof in an amount of from about 0.2 to about 20 wt% based on the composition, preferably wherein said antibody or antigen-binding fragment thereof is human or humanised;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 40 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition, preferably from about 40 to about 75 wt% based on the composition.

[0323] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 25 wt% based on the composition.

[0324] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0325] In any of the foregoing compositions, the antineoplastic antibody or antigen-binding fragment thereof is present in an amount of from about 0.2 to about 10 wt% based on the composition.

[0326] In any of the foregoing compositions, the organic solvent is preferably present in an amount of from about 50 to about 85 wt% based on the composition.

[0327] The compositions of the present disclosure may comprise at least one organic solvent. The term “organic solvent” as used herein is a term in the art. The organic solvent of the invention is not necessarily limited and a person skilled in the art of the present disclosure will be able to identify suitable organic solvents as part of their common general knowledge. The organic solvent is a pharmaceutically acceptable solvent or a biocompatible solvent. The solvent is suitable for administration to human or non-human animals.

[0328] In various embodiments, where present the organic solvent of the composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof comprises benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2- pyrrolidone, pyrrolidone-2, triacetin, tributyrin, tripropionin, and / or glycofurol.

[0329] In further embodiments, where present the organic solvent of the composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof is selected from benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2- pyrrolidone, pyrrolidone-2, triacetin, tributyrin, tripropionin, glycofurol or mixtures thereof.

[0330] In preferred embodiments, where present the organic solvent is selected from triproprionin, triacetin, and combinations thereof.

[0331] In various embodiments of the present disclosure, the composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof further comprises at least one pharmaceutically acceptable carrier or excipient.

[0332] Thus, in various embodiments the composition comprising at least one antineoplastic antibody comprises at least one excipient selected from buffers, tonicity agents / stabilisers, bulking agents, surfactants, antioxidants, metal ions / chelating agents, preservatives and combinations thereof. Such excipients are well known in the art and are for example described in Gokarn YR, et al. “Excipients for Protein Drugs. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems" Ashok K, Chaubal M, Eds. CRC Press: Boca Raton, FL, 2006; 291-332, and Chi EY. ‘Excipients Used in Biotechnology Products. Pharmaceutical Excipients: Properties, Functionality, and Applications in Research andIndustry.” Koo OMY, Ed. Wiley: Hoboken, NJ, 2016; 145-198, each of which is incorporated herein by reference.

[0333] For example, in various embodiments, the composition comprises at least one antineoplastic antibody comprises at least one sugar or polyol. For example, the composition may comprise glucose, sucrose, trehalose, sorbitol and / or glycerol.

[0334] In various embodiments, the composition comprises at least one surfactant, preferably a polysorbate surfactant, e.g. Tween® 80.

[0335] In various embodiments, the composition comprises at least one antioxidant, for example methionine.

[0336] In a preferred embodiment, the composition comprises at least one sugar, at least one surfactant, and at least one antioxidant. In a more preferred embodiment the composition comprises trehalose, a polysorbate surfactant, e.g. Tween® 80, and methionine.

[0337] In embodiments wherein the composition described hereinabove comprises a polyether-polyester copolymer (c) and an organic solvent (d) as defined herein, said composition provides a sustained release of the at least one antibody or antigen-binding fragment thereof. The term “sustained release” means that the active pharmaceutical ingredient can be released gradually over an extended period of time. This sustained release may be linear or non-linear and typically can last between several days to several weeks or more depending on the pharmaceutical composition and the amount of it administered. In various embodiments, the half-life of the at least one antibody or antigen-binding fragment thereof may be extended versus a composition not comprising the polyether-polyester copolymer (c) and organic solvent (d) as defined herein, e.g. versus a commercial formulation based on an aqueous solution or suspension of the antibody or antigen-binding fragment thereof. For example, the extended half-life of the antibody or antigen-binding fragment thereof may be up to about 1 month, up to about 2 months, or up to about 3 months. In further embodiments, the extended half-life of the antibody or antigen-binding fragment thereof may be at least about 3 weeks, at least about 4 weeks, at least about 5 weeks or at least about 6 weeks. In some embodiments, the extended half-life of the antibody or antigen-binding fragment thereof may be from about 6 to about 8 weeks.

[0338] In alternative embodiment, the composition comprising at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof is a commercially availableaqueous composition. For example, the composition may be any commercial product sold under the trade names detailed herein. In such embodiments the composition will be provided as formulated by the manufacturer and / or for which regulatory approval has been provided. Such compositions typically comprises an aqueous buffer, 10 to 200 mg / mL of the at least one antineoplastic monoclonal antibody or an antigen-binding fragment thereof and optionally at least one pharmaceutically acceptable excipient. A person skilled in the art will be able to identify such commercial products as part of their common general knowledge. In some embodiments, the composition may be supplied commercially as a composition ready for administration, for example as a composition for subcutaneous administration. In other embodiments, the composition may be supplied commercially as a composition for e.g. dilution prior to administration, such as in a saline solution for intravenous administration. Such dosage amounts may be based e.g. on the body weight of the subject to which the composition is to be administered. A person skilled in the art will be able to prepare such compositions as part of their common general knowledge, general clinical practice and based on product labels and information supplied with such commercial compositions.(b) Compositions comprising at least one small-molecule antineoplastic agent

[0339] As described herein, aspects of the present disclosure provide a combination comprising a first composition and a second composition as defined herein. The second composition comprises at least one small-molecule antineoplastic agent.

[0340] The at least one small-molecule antineoplastic agent of any of the compositions defined herein above may be a small-molecule antineoplastic agent as defined in any of the embodiments disclosed herein.

[0341] Thus in various embodiments the present disclosure provides a composition comprising at least at least one small-molecule antineoplastic agent, preferably wherein said at least one small-molecule antineoplastic agent is selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. Preferably, the at least one small-molecule antineoplastic agent is selected from protein kinase inhibitors, TLR agonists, and combinations thereof. The TLR agonist may be selected from TLR-7, TLR-8 and TLR-7 / 8 agonists. Preferably, the TLR agonist is selected from imiquimod, resiquimod, pharmaceutically acceptable derivatives thereof, and combinations thereof. The protein kinase inhibitor may inhibit the MAPK signalling pathway, for example the protein kinase inhibitor may inhibit MEK, and / or RAF. In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments theprotein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof. In further embodiments, the protein kinase inhibitor comprises a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0342] In various embodiments, the first composition may comprise at least one polyetherpolyester copolymer, wherein the copolymer has the formula:B(A)n wherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.

[0343] Thus, a further aspect of the present disclosure provides a pharmaceutical composition comprising:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0344] The at least one polyether-polyester copolymer of any of the foregoing compositions may be as defined in any of the embodiments described herein.

[0345] For example, one embodiment of the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0346] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0347] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0348] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0349] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0350] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0351] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0352] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent.

[0353] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0354] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0355] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0356] In any of the foregoing compositions the at least one polyether-polyester copolymer is present in the pharmaceutical composition in an amount of from about 10 to about 75 wt% based on the composition, preferably from about 10 to about 40 wt% based on the composition.

[0357] In any of the foregoing compositions when the at least one polyether-polyester is a mixture of a triblock copolymer and a diblock copolymer, each of the copolymers is present in an amount of from 5 to 40 wt% based on the composition, preferably from about 10 to 25% based on the composition.

[0358] Thus, one embodiment of the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyetherarm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0359] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0360] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0361] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0362] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyetherarm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0363] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0364] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0365] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0366] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyetherarm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0367] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0368] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0369] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0370] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0371] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0372] In any of the foregoing compositions, the organic solvent may be present in the composition in an amount of from about 15 to about 85 wt%, preferably from about 40 to about 75 wt%, more preferably from about 50 to about 85 wt%, based on the composition.

[0373] Thus, one embodiment of the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0374] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0375] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0376] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0377] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0378] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0379] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the second composition.

[0380] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0381] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0382] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or apharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0383] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0384] In any of the foregoing embodiments, the organic solvent may be present in an amount of from about 40 to about 75 wt% based on the composition.

[0385] In one embodiment the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0386] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0387] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0388] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0389] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0390] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Azwherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0391] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0392] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0393] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0394] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0395] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0396] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0397] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0398] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0399] In any of the foregoing embodiments, the organic solvent may be present in an amount of from about 40 to about 75 wt% based on the composition.

[0400] In various embodiments, the small-molecule antineoplastic agent is present in the composition in an amount of from about 0.2 to about 30 wt% based on the composition.

[0401] one embodiment of the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0402] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0403] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0404] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0405] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0406] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0407] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0408] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent.

[0409] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent.

[0410] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0411] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments theprotein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0412] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0413] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0414] In one embodiment of the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0415] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Azwherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0416] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0417] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0418] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Azwherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0419] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0420] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the second composition.

[0421] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Azwherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0422] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0423] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0424] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0425] In one embodiment the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0426] In another embodiment, the pharmaceutical composition comprises:(i) at least one small-molecule antineoplastic agent in an amount of from about 0.2 to about 30 wt% based on the composition;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0427] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0428] In any of the preceding embodiments, the at least one small-molecule antineoplastic agent may be selected from immune response modifiers, protein kinase inhibitors, and combinations thereof. In particular, the at least one small-molecule antineoplastic agent may be selected from protein kinase inhibitors, TLR agonists, and combinations thereof.

[0429] Thus, in preferred embodiments, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0430] In another embodiment, the pharmaceutical composition comprises:(i) at least one TLR agonist in an amount of from about 0.2 to about 30 wt% based on the composition, preferably a TLR-7, TLR-8, or TLR-7 / 8 agonist;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0431] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0432] In particularly preferred embodiments the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0433] In other embodiments, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a multi-arm copolymer in an amount of from about 10 to about 75 wt% based on the composition, the copolymer having 3 to 8 polyester arms attached to a centralcore which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0434] In another embodiment, the pharmaceutical composition comprises:(i) at least one protein kinase inhibitor in an amount of from about 0.2 to about 30 wt% based on the composition, which preferably inhibits the MAPK signalling pathway;(ii) a mixture of a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000; wherein the mixture is present in an amount of from about 10 to about 75 wt% based on the composition; and(iii) an organic solvent in an amount of from about 15 to about 85 wt% based on the composition.

[0435] Preferably, each of the triblock copolymer and the diblock copolymer is present in an amount of from about 5 to about 40 wt% based on the composition.

[0436] In preferred embodiments the protein kinase inhibitor is selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In other embodiments the protein kinase inhibitor is selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

[0437] As disclosed herein, the protein kinase inhibitor may comprise a first protein kinase inhibitor, e.g. dabrafenib, encorafenib, or pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor, e.g. trametinib, cobimetinib, binimetinib, or a pharmaceutically acceptable derivative thereof. In particularly preferred embodiments, the protein kinase inhibitor comprises dabrafenib and trametinib.

[0438] In any of the foregoing compositions, the polyester of the polyether-polyester copolymer is preferably poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA), more preferably PLA, and the end-capped polyethylene glycol is preferably methoxy-polyethylene glycol.

[0439] In any of the foregoing embodiments, the organic solvent may be present in an amount of from about 40 to about 75 wt% based on the composition.

[0440] In any of the foregoing compositions, the organic solvent is preferably present in an amount of from about 50 to about 85 wt% based on the composition.

[0441] The compositions of the present disclosure may comprise at least one organic solvent. The term “organic solvent” as used herein is a term in the art. The organic solvent of the invention is not necessarily limited and a person skilled in the art of the present disclosure will be able to identify suitable organic solvents as part of their common general knowledge. The organic solvent is a pharmaceutically acceptable solvent or a biocompatible solvent. The solvent is suitable for administration to human or non-human animals.

[0442] In various embodiments, the organic solvent of the composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof comprises benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl- 2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, triacetin, tributyrin, tripropionin, and / or glycofurol.

[0443] In further embodiments, the organic solvent of the composition comprising at least one antineoplastic antibody or antigen-binding fragment thereof is selected from benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl- 2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, triacetin, tributyrin, tripropionin, glycofurol or mixtures thereof; preferably wherein the organic solvent is DMSO or tripropionin.

[0444] In preferred embodiments, the organic solvent is selected from DMSO, NMP and combinations thereof.

[0445] In various embodiments of the present disclosure, the composition comprising at least one small molecule antineoplastic agent further comprises at least one pharmaceutically acceptable carrier or excipient. Such carriers and excipients are well known in the art, for example in “Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21stEdition, (2005).Combinations

[0446] In one aspect, the present disclosure provides a combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0447] In some embodiments, the combination may consist of:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent;wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0448] As described herein, it has surprisingly been found that the compositions of the present disclosure comprising the at least one polyether-polyester copolymer as defined herein can be used for sustained release of small-molecule antineoplastic agents as well as antineoplastic antibodies. Thus, the at least polyether-polyester copolymer may be included in the first and / or second compositions of the combination.

[0449] Accordingly, in one embodiment of the combination, the second composition comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0450] In such cases, the first composition may not comprise the at least one polyether- polyester copolymer as defined by component (c). In such embodiments, the composition will generally not comprise the at least one organic solvent (d). In such embodiments the composition is typically in the form of an aqueous solution or suspension. For example, the composition may be formulated for intravenous or subcutaneous administration. In various embodiments, the composition may be formulated for dilution into e.g. saline prior to intravenous administration as commonly practiced in the art. Such compositions are commercially available and will be readily identified by persons skilled in the art of the present disclosure.

[0451] In an alternative embodiment, the first composition comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0452] In such cases, the second composition may not comprise the at least one polyether- polyester copolymer as defined by component (c). In such embodiments, the composition will generally not comprise the at least one organic solvent (d). In such embodiments the composition is typically in the form of an aqueous solution or suspension. For example, the composition may be formulated for intravenous or subcutaneous administration. In various embodiments, the composition may be formulated for dilution into e.g. saline prior to intravenous administration as commonly practiced in the art. Such compositions are commercially available and will be readily identified by persons skilled in the art of the present disclosure.

[0453] In another embodiment, each of the first and second composition independently comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0454] In certain embodiments, the at least one polyether-polyester copolymer may be the same for the first composition and the second composition. Alternatively, and more preferably, the at least one polyether-polyester copolymer of the first composition is different from the at least one polyether-polyester copolymer of the second composition. Each of the at least one polyether-polyester copolymers may be a copolymer according to any of the embodiments disclosed herein.

[0455] The first composition of the combination may be any of the compositions comprising at least one antineoplastic antibody or antigen-binding fragment thereof as defined herein. Similarly, the second composition of the combination may be any of the compositions comprising at least one small-molecule antineoplastic agent as defined herein. Moreover, the skilled person will understand that any first composition as defined herein may be combined with any second composition as defined herein to provide a combination according to the present disclosure. In particular, a person skilled in the art will be able to make such combinations as part of their common general knowledge, e.g. in view of a particular approved indication or investigational indication for the treatment of a subject in need thereof. The number of compositions in the combination is not necessarily limited and it will be appreciated that in various embodiments described herein it may be desirable that the combination comprises one or more additional compositions, e.g. a third composition, as further defined herein.

[0456] In various embodiments, the small-molecule antineoplastic agent is a TLR agonist, preferably a TLR-7, TLR-8 or TLR-7 / 8 agonist, and the antineoplastic antibody or antigenbinding fragment thereof is an anti-TYRP1 antibody or antigen-binding fragment thereof, more preferably flanvotumab or an antigen-binding fragment thereof.

[0457] In other embodiments, the small-molecule antineoplastic agent is a BRAF or MEK inhibitor, preferably a combination of a BRAF inhibitor and a MEK inhibitor, and the antineoplastic antibody or antigen-binding fragment thereof is an anti-TYRP1 antibody or antigen-binding fragment thereof, preferably flanvotumab or antigen-binding fragment thereof. Preferably, the BRAF inhibitor is dabrafenib and the MEK inhibitor is trametinib. Thus, in a particularly preferred embodiment the small-molecule antineoplastic agent comprises or is a combination of dabrafenib and trametinib and the antineoplastic antibody or antigen-binding fragment comprises or is flanvotumab. In other embodiments, the BRAF inhibitor and MEK inhibitor are comprised as separate compositions within the combination of the present disclosure. For example, the BRAF inhibitor may be comprised in the first composition of the combination and the MEK inhibitor may be comprised in a third composition of the combination or vice versa.

[0458] In various embodiments, the small-molecule antineoplastic agent is a TLR agonist, preferably a TLR-7, TLR-8 or TLR-7 / 8 agonist, and the antineoplastic antibody or antigenbinding fragment thereof is an anti-PD-1 , anti-PD-L1 , or anti-CTLA-4 antibody or antigenbinding fragment thereof, more preferably nivolumab, pembrolizumab, atezolizumab,cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab or an antigen-binding fragment thereof.

[0459] In other embodiments, the small-molecule antineoplastic agent is a BRAF or MEK inhibitor, preferably a combination of a BRAF inhibitor and a MEK inhibitor, and the antineoplastic antibody or antigen-binding fragment thereof is an anti-PD-1 , anti-PD-L1 , or anti- CTLA-4 antibody or antigen-binding fragment thereof, nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab or an antigenbinding fragment thereof. Preferably, the BRAF inhibitor is dabrafenib and the MEK inhibitor is trametinib. Thus, in a particularly preferred embodiment the small-molecule antineoplastic agent comprises or is a combination of dabrafenib and trametinib. In other embodiments, the BRAF inhibitor and MEK inhibitor are comprised as separate compositions within the combination of the present disclosure. For example, the BRAF inhibitor may be comprised in the first composition of the combination and the MEK inhibitor may be comprised in a third composition of the combination or vice versa.

[0460] In some embodiments, the combination may consist of the first composition and second composition according to any of the embodiments disclosed herein. However, as noted herein above, in other embodiments the combination may comprise a further composition, for example a third composition. The further composition may comprise at least one further antineoplastic antibody and / or a small-molecule antineoplastic agent. Typically, the at least one further antineoplastic antibody and / or a small-molecule antineoplastic agent will be different from each of the antineoplastic antibody of the first composition and the smallmolecule antineoplastic agent of the second composition. The further composition may comprise at least one polyether-polyester copolymer as defined herein and at least one organic solvent as defined herein. In other embodiments, the further composition does not comprise the at least one polyether-polyester copolymer defined herein and in such embodiments will typically also not comprise the at least one organic solvent defined herein. Exemplary and nonlimiting examples of the at least one further antineoplastic antibody and / or antineoplastic agent include:

[0461] Alkylating Agents: e.g. Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurbinectedin, Mechlorethamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedin;

[0462] Platinum Coordination Complexes: e.g. Carboplatin, Cisplatin, Oxaliplatin;

[0463] Cytotoxic antibiotics: e.g. Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Valrubicin;

[0464] Antimetabolites: e.g. Antifolates (e.g. Methotrexate, Pemetrexed, Pralatrexate, Trimetrexate); Purine Analogues (e.g. Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Thioguanine); Pyrimidine Analogues (e.g. Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Gemcitabine, Trifluridine / Tipracil)

[0465] Biologic Response Modifiers: e.g. Aldesleukin (IL-2), Denileukin Diftitox, Interferon Gamma

[0466] Histone Deacetylase Inhibitors: e.g. Belinostat, Panobinostat, Romidepsin, Vorinostat

[0467] Hormonal Agents: e.g. Antiandrogens (Abiraterone, Apalutamide, Bicalutamide, Cyproterone, Enzalutamide, Flutamide, Nilutamide); Antiestrogens including Aromatase Inhibitors (e.g. Anastrozole, Exemestane, Fulvestrant, Letrozole, Raloxifene, Tamoxifen, Toremifene); Gonadotropin Releasing Hormone Analogues (e.g. Degarelix, Goserelin, Histrelin, Leuprolide, Relugolix, Triptorelin); Peptide Hormones (e.g. Lanreotide, Octreotide, Pasireotide);

[0468] Monoclonal Antibodies: e.g. Alemtuzumab, Atezolizumab, Avelumab, Bevacizumab, Blinatumomab, Brentuximab, Cemiplimab, Cetuximab, Daratumumab, Dinutuximab, Dostarlimab, Durvalumab, Elotuzumab, Fianlimab, Gemtuzumab, Inotuzumab Ozogamicin, Ipilimumab, Mogamulizumab, Moxetumomab Pasudotox, Necitumumab, Nivolumab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Ramucirumab, Relatlimab, Rituximab, Teclistamab, Tiragolumab, Tositumomab, Trastuzumab, Tremelimumab, Vibostolimab;

[0469] Protein Kinase Inhibitors: e.g. Abemaciclib, Acalabrutinib, Adagrasib, Afatinib, Alectinib, Alpelisib, Axitinib, Binimetinib, Bortezomib, Bosutinib, Brigatinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Copanlisib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duvelisib, Enasidenib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Fedratinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Ibrutinib, Idelalisib, Imatinib, Infigratinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Ponatinib, Regorafenib, Ribocicib, Rucaparib, Ruxolitinib, Selumetinib, Sonidegib, Sorafenib, Sotorasib,Sunitinib, Talazoparib, Temuterkib, Trametinib, Vandetanib, Vemurafenib, Vismodegib, Zanubrutinib;

[0470] Taxanes: e.g. Cabazitaxel, Docetaxel, Paclitaxel;

[0471] Topoisomerase Inhibitors: e.g. Etoposide, Irinotecan, Teniposide, Topotecan;

[0472] Vinca Alkaloids: e.g. Vinblastine, Vincristine, Vinorelbine;

[0473] Miscellaneous: e.g. Asparaginase (Pegaspargase), Belzutifan, Bexarotene, Cedazuridine, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Mitotane, Omacetaxine, Pomalidomide, Selinexor, Tagraxofusp, Tazemetostat, Tebentafusp, Telotristat, Temsirolimus, Thalidomide, Venetoclax.

[0474] The additional composition may also comprise e.g. cytokine-related therapies, immune cell-based therapies (such as chimeric antigen receptor T cell (CAR-T) therapies), cancer vaccines (active and passive), antibody-drug conjugates, bispecific antibodies, oncolytic viruses, and other immunity-based technologies.

[0475] Other possible combinations of small-molecule antineoplastic agents and / or antineoplastic antibodies will be apparent to a person skilled in the art, who is able to identify such combinations on the basis of their common general knowledge e.g. in view of approved indications and / or clinical trials. In particular, any of the antibody combinations described herein may be provided as separate compositions in the combination of the present disclosure, for example combinations of anti-PD-1 or anti-PD-L1 antibodies with anti-CTLA-4 antibodies, combinations of anti-PD-1 or anti-PD-L1 antibodies with anti-LAG3 antibodies, or combinations of anti-PD-1 or anti-PD-L1 antibodies with anti-TIGIT antibodies as described herein may be provided as separate compositions, e.g. as a first composition and a third composition as described herein. Similarly, any of the small-molecule combinations disclosed herein, such as combinations of BRAF and MEK inhibitors, may be supplied as separate compositions, e.g. as a second composition and a third composition as described herein.

[0476] Formulations of the present disclosure include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intrathecal, intramuscular e.g. by depot and intravenous), and rectal or in a form suitable for administration by inhalation or insufflation administration. The most suitable route of administration may depend upon the condition and disorder of the patient.

[0477] Compositions not comprising a copolymer according to the present disclosure, and particularly compositions comprising small-molecule actives, may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in “Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21stEdition, (2005). Suitable methods include the step of bringing into association to active ingredients with a carrier which constitutes one or more excipients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. It will be appreciated that when the two active ingredients are administered independently, each may be administered by a different means.

[0478] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration), each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil- in-water liquid emulsion or water-in-oil liquid emulsion. The active ingredients may also be presented as a bolus, electuary or paste.

[0479] A tablet may be made by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with other conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, polyvinylpyrrolidone and / or hydroxymethyl cellulose), fillers (e.g. lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate and / or sorbitol), lubricants (e.g. magnesium stearate, stearic acid, talc, polyethylene glycol and / or silica), disintegrants (e.g. potato starch, croscarmellose sodium and / or sodium starch glycolate) and wetting agents (e.g. sodium lauryl sulphate). Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide controlled release (e.g. delayed, sustained, or pulsed release, or a combination of immediate release and controlled release) of the active ingredients.

[0480] Alternatively, the active ingredients may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Formulationscontaining the active ingredients may also be presented as a dry product for constitution with water or another suitable vehicle before use.

[0481] Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and / or hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan mono-oleate and / or acacia), non-aqueous vehicles (e.g. edible oils, such as almond oil, fractionated coconut oil, oily esters, propylene glycol and / or ethyl alcohol), and preservatives (e.g. methyl or propyl p-hydroxybenzoates and / or sorbic acid).

[0482] Compositions not comprising a copolymer according to the present disclosure, and particularly compositions comprising antibodies, may be formulated for parenteral administration, for example as an injectable composition or a composition for intravenous administration. In specific embodiments, the composition may be formulated as a powder or liquid composition for dilution, e.g. into saline prior to intravenous administration.

[0483] In various embodiments, any of the compositions disclosed herein may be an injectable composition. For example, in preferred embodiments, the first composition of the combination is an injectable composition.

[0484] In other preferred embodiments, the second composition of the combination is an injectable composition.

[0485] In other embodiments, both the first and second composition may be injectable compositions.

[0486] In various embodiments, any of the compositions disclosed herein, whether they comprise a polyether-polyester copolymer according to the present disclosure or not, may be administered by subcutaneous, peri-tumoral or intra-tumoral injection. Preferably, the composition is administered by peri-tumoral or intra-tumoral injection, and more preferably by peri-tumoral injection.

[0487] The terms “subcutaneous”, “peri-tumoral” and “intra-tumoral” are terms in the art. As used herein, the term “subcutaneous” takes it normal meaning, i.e. that the injection is applied under the skin (typically into fatty tissue just under the skin). The term “peri-tumoral” refers to administration e.g. of the composition(s) disclosed herein around the tumor, i.e. in the local area surrounding the tumor. The term “intra-tumoral” refers to administration, e.g. by injection,into the tumor mass itself. Such modes of administration are commonly practice in the art of the present disclosure and a skilled person will be able to identify suitable equipment for such a procedure, which they are able to carry out as part of their common general knowledge, skills and expertise in the field of the present invention.

[0488] Compositions as defined herein comprising said polyether-polyester copolymer may be liquid at room temperature. For example, in preferred embodiments the compositions may be liquid at room temperature and form a semi-solid or solid implant when injected into an aqueous environment. Compositions according to the present disclosure may, for example, be liquid at room temperature and form a semi-solid or solid implant when administered by subcutaneous, peri-turmoral or intra-tumoral injection. In particular, compositions comprising a copolymer according to the present disclosure may be liquid at room temperature and form a semi-solid or solid implant when administered by subcutaneous, peri-turmoral or intra-tumoral injection, preferably peri-tumoral administration.

[0489] For example, in a preferred embodiment a composition according to the present disclosure comprises at least one small-molecule antineoplastic agent that is a TLR agonist, and at least one polyether-polyester copolymer as defined herein, is suitable for subcutaneous, peri-tumoral or intra-tumoral administration, e.g. peritumoral or intra-tumoral injection.

[0490] In various embodiments of the present disclosure, the first and second compositions may be simultaneously, separately, or sequentially administered. Where the combination comprises one or more further compositions, two or more of said compositions may be simultaneously, separately, or sequentially administered.Use in therapy

[0491] It will be appreciated that references herein to “treatment" extend to prophylaxis as well as the treatment of established diseases or symptoms.

[0492] The compositions and compositions disclosed herein and particularly suitable for the treatment of cancers, and in particular solid tumors.

[0493] Accordingly, in various aspects the present disclosure provides any of the compositions and combinations disclosed herein for use in treating a solid tumor in a subject.

[0494] Thus, in one embodiment the present disclosure provides a combination for use in treating a solid tumor in a subject, said combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0495] The combination may be further defined according to any of the embodiments set out herein above.

[0496] In another embodiment, the present disclosure provides a pharmaceutical composition for use in the treatment of a solid tumor in a subject, the composition comprising:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), eachA represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0497] Said composition may be further defined according to any of the embodiments set out herein above.

[0498] In another embodiment the present disclosure provides a pharmaceutical composition for use in treating a solid tumor in a subject, the composition comprising:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.

[0499] Said composition may be further defined according to any of the embodiments set out herein above.

[0500] Also provided is the use of any of the combinations and compositions as defined herein in the manufacture of a medicament for the treatment of a solid tumor in a subject.

[0501] Also provided are methods of treating a solid tumor in a subject, the method comprising administering to the subject a composition or combination as disclosed herein.

[0502] For example, an aspect of the present disclosure provides a method of treating a solid tumor in a subject, the method comprising administering to the subject:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

[0503] The first and / or second composition in the foregoing method may be further defined according to any of the embodiments disclosed herein.

[0504] In various embodiments of the foregoing method, the first composition and the second composition are administered separately, sequentially or simultaneously to the subject.

[0505] The nature of the solid tumor is not limited. In any of the foregoing aspects and embodiments, the solid tumor may be a pancreatic cancer, colorectal cancer, non-small cell lung cancer, pleural cancer, peritoneal carcinomatosis, mesothelioma, bladder cancer, breast cancer or melanoma. For instance, the combinations disclosed herein may be particularly effective against melanoma, and in particular advanced stage melanoma. As used herein, “advanced stage” refers to cancer that has spread from where it started to at least one other part of the body, i.e. a metastasized cancer. Advanced melanoma may also be referred to as stage 4 melanoma, for instance.

[0506] In various embodiments, the tumor may be positive for one or more driver mutations. For instance, mutations in BRAF are present in 37 to 50% of melanomas, mutations in NRAS are present in 13 to 25% of melanomas, mutations in tMEK are present in 6 to 7% of melanomas, mutations in KIT are present in 2 to 8% of melanomas, mutations in CTTNB1 are present in 2 to 4% of melanomas, mutations in GNA11 are present in about 1% of melanomas and mutations in GNAQ are present in about 1% of melanomas.

[0507] Thus, in various embodiments, the tumor may comprise at least one BRAF, NRAS, MEK, KIT, CTTNB1 , GNA11 and / or GNAQ mutation. In preferred embodiments, the tumor comprises at least one BRAF and / or MEK mutation.

[0508] In other embodiments, the tumor may comprise at least one KRAS and / or HRAS mutation. For example, the tumor may comprise a KRAS G12C mutation.

[0509] Targeted therapies are generally indicated for use against cancers positive for one or more specific mutations, e.g. driver mutations. For instance, targeted therapies for the treatment of melanoma may be indicated for the treatment of tumors comprising (i.e. positive for) at least one mutation in BRAF.

[0510] In particular, the tumor may comprise at least one BRAF V600 mutation. Mutations at position V600 in BRAF are particularly common in melanomas and tumors comprising such mutations may be particularly susceptible to targeted therapies such as BRAF and / or MEK inhibition. Of the melanomas harbouring BRAF driver mutations, the most common (estimated to be over 90%) of such mutations is the V600E mutation.

[0511] Such tumors may be advantageously treated with targeted therapies. Thus, in various embodiments the tumor comprises at least one BRAF mutation, e.g. a BRAF V600 mutation, and the small-molecule antineoplastic agent is a kinase inhibitor. Particularly preferred kinase inhibitors for such indications include BRAF and MEK inhibitors. Thus, in various embodiments of the compositions and combinations for use according to the present disclosure, the tumor comprises at least one BRAF mutation, e.g. a BRAF V600 mutation, and the small-molecule antineoplastic agent is a BRAF inhibitor. In other embodiments, the tumor comprises at least one BRAF mutation, e.g. a BRAF V600 mutation, and the small-molecule antineoplastic agent is a MEK inhibitor. In particularly preferred embodiments, the combination for use comprises a combination of a BRAF inhibitor and a MEK inhibitor. The combination of a BRAF inhibitor and a MEK inhibitor may be comprise in a single composition, e.g. the second composition of the combination (which may comprise a first protein kinase inhibitor and a second protein kinase inhibitor as defined herein), or each of the BRAF inhibitor and MEK inhibitor may be present as separate compositions in the combination. As such, the BRAF and MEK inhibitor may be separately, sequentially, or simultaneously administered, e.g. to the subject.

[0512] In various embodiments the BRAF inhibitor may be selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. In various embodiments the MEK inhibitor may be selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof. In particularly preferred embodiments, the BRAF inhibitor is dabrafenib or a pharmaceutically acceptable derivative thereof, and the MEK inhibitor is trametinib or a pharmaceutically acceptable derivative thereof. Such combinations may preferably be used for treating melanoma, particularly an advanced stage melanoma.

[0513] In other embodiments, the tumor may not comprise (i.e. be negative) a mutation in BRAF and / or MEK. For example, the tumor may be negative for mutations in each of BRAF, KIT and NRAS, for example a melanoma negative for mutations in each of BRAF, KIT and NRAS (commonly referred to as “triple negative melanoma” in the art).

[0514] For such tumors, particularly preferred small-molecule antineoplastic agents are immune response modifiers, e.g. TLR agonists, more preferably TLR-7, TLR-8, and TLR-7 / 8 agonists. For example, the TLR agonist may be selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

[0515] In any of the foregoing embodiments, the antineoplastic antibody or antigen-binding fragment thereof may be an anti-TYRP1 antibody or antigen-binding fragment thereof. In particular, such an antibody or antigen-binding fragment thereof may advantageously be usedcombinations for use in treating a solid tumor expressing TYRP1 that does not comprise a mutation in BRAF and / or MEK, e.g. a tumor negative for mutations in each of BRAF, KIT and NRAS, such as a triple negative melanoma. Such an antibody or antigen-binding fragment may also be advantageously used in combinations for use in treating a solid tumor that comprises a mutation in BRAF and / or MEK, e.g. a BRAF V600 mutation.

[0516] For example, in various embodiments, the small-molecule antineoplastic agent is a TLR agonist, preferably a TLR-7, TLR-8 or TLR-7 / 8 agonist, and the antineoplastic antibody or antigen-binding fragment thereof is an anti-TYRP1 antibody or antigen-binding fragment thereof, more preferably flanvotumab or an antigen-binding fragment thereof. In various embodiments, such a combination is for use in treating a solid tumor that is negative for mutations in BRAF and / or MEK, in particular a solid tumor that is negative for mutations in each of BRAF, KIT and NRAS, e.g. a triple negative melanoma.

[0517] In other embodiments, the small-molecule antineoplastic agent is a BRAF or MEK inhibitor, preferably a combination of a BRAF inhibitor and a MEK inhibitor, and the antineoplastic antibody or antigen-binding fragment thereof is an anti-TYRP1 antibody or antigen-binding fragment thereof, preferably flanvotumab or antigen-binding fragment thereof. Preferably, the BRAF inhibitor is dabrafenib and the MEK inhibitor is trametinib. Thus, in a particularly preferred embodiment the small-molecule antineoplastic agent comprises or is a combination of dabrafenib and trametinib and the antineoplastic antibody or antigen-binding fragment comprises or is flanvotumab. In such preferred combinations, the tumor preferably comprises a mutation in BRAF and / or MEK, in particular BRAF, e.g. a melanoma comprising a BRAF V600 mutation. In other embodiments, the BRAF inhibitor and MEK inhibitor are comprised as separate compositions within the combination of the present disclosure. For example, the BRAF inhibitor may be comprised in the first composition of the combination and the MEK inhibitor may be comprised in a third composition of the combination or vice versa.

[0518] In any of the foregoing embodiments, the antineoplastic antibody or antigen-binding fragment thereof may be an anti-PD-1 , anti-PD-L1 , or anti-CTLA-4 antibody or antigen-binding fragment thereof. In particular, such an antibody or antigen-binding fragment thereof may advantageously be used combinations for use in treating a solid tumor that does not comprise a mutation in BRAF and / or MEK, e.g. a tumor negative for mutations in each of BRAF, KIT and NRAS, e.g. a triple negative melanoma. Such an antibody or antigen-binding fragment may also be advantageously used in combinations for use in treating a solid tumor that comprises a mutation in BRAF and / or MEK, e.g. a BRAF V600 mutation.

[0519] For example, in various embodiments, the small-molecule antineoplastic agent is a TLR agonist, preferably a TLR-7, TLR-8 or TLR-7 / 8 agonist, and the antineoplastic antibody or antigen-binding fragment thereof is an anti-PD-1 , anti-PD-L1 , or anti-CTLA-4 antibody or antigen-binding fragment thereof, more preferably nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab or an antigen-binding fragment thereof.

[0520] In other embodiments, the small-molecule antineoplastic agent is a BRAF or MEK inhibitor, preferably a combination of a BRAF inhibitor and a MEK inhibitor (which may be comprised in a single composition or separate compositions), and the antineoplastic antibody or antigen-binding fragment thereof is an anti-PD-1 , anti-PD-L1 , or anti-CTLA-4 antibody or antigen-binding fragment thereof, nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab or an antigen-binding fragment thereof. Preferably, the BRAF inhibitor is dabrafenib and the MEK inhibitor is trametinib. Thus, in a particularly preferred embodiment the small-molecule antineoplastic agent comprises or is a combination of dabrafenib and trametinib. In such preferred combinations, the tumor preferably comprises a mutation in BRAF and / or MEK, in particular BRAF, e.g. a melanoma comprising a BRAF V600 mutation.

[0521] As described herein, any of the foregoing compositions and combinations for use may be further defined according to the embodiments described herein, in particular in respect of embodiments relating to the copolymer, organic solvent, and / or amounts of the antineoplastic agents, copolymer and / or organic solvent.

[0522] As described herein, the compositions and combinations disclosed herein may be suitable for separate, sequential or simultaneous administration. Thus, in various embodiments of the method described above, the first composition and the second composition are administered separately, sequentially or simultaneously to the subject. In various embodiments, the combination may comprise at least one further composition as disclosed herein. In such embodiments, at least two of the compositions comprised in the combination may be administered separately, sequentially or simultaneously to the subject.

[0523] The amount of active ingredients required for use in treatment will vary with the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, e.g. as two, three or more sub-doses per day. As discussed herein, compositions comprising at least onepolyether-polyester copolymer according to the present disclosure advantageously provide sustained release of the antineoplastic agent, e.g. small-molecule, antibody or antigen-binding fragment thereof. Thus, such compositions advantageously remove the need for multiple subdoses, and so may be administered as a single dose.

[0524] In a preferred embodiment the compositions are injected using a needle and syringe, optionally using an injection device. Typical volumes of injection of the composition administered to a subject are 0.05 mL to 5 mL or 0.1 to 1.5 mL.

[0525] The subject may be an animal. The term “animals” encompasses all members of the Kingdom Animalia. The animal may be a human or non-human animal.Kit of parts

[0526] Various aspects of the present disclosure provide kits of parts comprising the compositions and combinations disclosed herein.

[0527] For example, one aspect of the present disclosure provides a kit of parts comprising:(A) a prefilled syringe comprising a first injectable composition, wherein the injectable composition comprises:- at least one antineoplastic antibody or an antigen-binding fragment thereof, or at least one small-molecule antineoplastic agent;- at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.(B) at least one needle; and(C) instructions for use.

[0528] In various embodiments, the first injectable composition comprises at least one antineoplastic antibody, and the kit further comprises (D) a second composition comprising at least one small-molecule antineoplastic agent.

[0529] In other embodiments, the first injectable composition comprises at least one smallmolecule antineoplastic agent, and the kit further comprises (D) a second composition comprising at least one antineoplastic antibody.

[0530] In various embodiments the second composition is comprised in a prefilled syringe and said second composition is an injectable composition further comprising: at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.

[0531] In alternative embodiments the second composition is comprised in a prefilled syringe and said second composition is an injectable aqueous composition further comprising: at least one buffer; and optionally one or more pharmaceutically acceptable excipients.

[0532] In any of the foregoing embodiments, the antineoplastic antibody or antigen-binding fragment thereof, small-molecule antineoplastic agent, polyether-polyester copolymer, and / or organic solvent may be further defined according to any of the embodiments disclosed herein above.

[0533] The needle may be any needle suitable for the mode of administration. For example, the needle may be suitable for administration by subcutaneous, peri-tumoral, or intra-tumoral injection. A person skilled in the art will be able to identify suitable needles as part of their common general knowledge.

[0534] In various embodiments, the needle has a gauge number equal to or greater than 21. In various embodiments, the length of the needle may be equal to or shorter than 1.5 inches (3.8 cm). In further embodiments, the needle has a gauge number equal to or greater than 21 and the length of the needle is equal to or shorter than 1.5 inches (3.8 cm).

[0535] Having generally described this disclosure, a further understanding can be obtained by reference to certain specific examples illustrated below which are provided for purposes of illustration only and are not intended to be all inclusive or limiting unless otherwise specified.ExamplesExample 1 : MaterialsCopolymer synthesis

[0536] Copolymers were synthesized according to the method described in the US 6,350,812, and WO 2020 / 144239 (each of which is incorporated herein by reference), with minor modifications.

[0537] Typically, the necessary amount of PEG (to give a triblock copolymer), methoxy-PEG (to give a diblock copolymer) or multi-branched-PEG (to give a multi-branched copolymer) were mixed with D,L-lactide (corresponding to the targeted LA / EO molar ratio) and catalyst (1 / 1000 of amount of lactide) in a reaction vessel. The reaction mixture was first dehydrated by several short vacuum / nitrogen cycles. The reaction mixture was then heated and rapidly degassed under vacuum. The reaction was conducted for several hours to several days at constant temperature under constant nitrogen flow (0.2 bar). The reaction was cooled to room temperature and its content was dissolved in acetone and then subjected to precipitation with a non-solvent of the block copolymer, e.g. ethanol. The product obtained was subsequently dried under reduced pressure. Alternatively, the copolymers may be purchased from Corbion.

[0538] The product obtained was characterized by 1 H NMR for its residual lactide content and for the determination of the R ratio. 1 H NMR spectroscopy was performed using a Bruker Advance 300 MHz spectrometer. For all 1 H NMR spectrograms, TopSpin software was used for the integration of PLA and PEG characteristic peaks and their analyses. Chemical shifts were referenced to the 8 = 7.26 ppm solvent value of CDCh.

[0539] The product obtained was further characterized by gel permeation chromatography (GPC) for the determination of its molecular weight distribution. GPC was performed using a LC system equipped with a refractive index detector. The equipment can be equipped with a series of Waters styragel columns selected from HR4, HR3 HR2 and HR1 kept at constant temperature. Samples were run in BHT-stabilized THF at a constant flow rate. Molecular weight distributions (Mn; Mw and polydispersity index) were determined by conventional calibration using polystyrene calibration standards.

[0540] For the preparation of alternative copolymers, further monomers are used such as epsilon-caprolactone or glycolide with minor modifications. Alternatively, the copolymers may be purchased from Corbion.

[0541] The triblock, diblock and multi-branched copolymers described herein are respectively labelled PaRb, dPaRb and sxPaRb, where a represents the size of the PEG chain / core in kDa, b is the LA / EO molar ratio and x represents the number of arms of the multi-branched copolymer.Active pharmaceutical ingredients

[0542] TA99 mAb was obtained from Bio X Cell (Lebanon, New Hampshire) as a protein solution in PBS (phosphate-buffered saline).

[0543] Imiquimod, vemurafenib, dabrafenib and trametinib were obtained from CliniSciences (Nanterre, France).Example 2: Long-acting formulations - preparationSmall molecules formulation preparation

[0544] A polymeric vehicle was prepared by solubilizing the required amount of copolymers in organic solvent, e.g. DMSO, to reach the final polymer content. After full solubilization of copolymers, the required amount of active pharmaceutical ingredient was added to the vehicle to achieve the targeted loading. Formulations were then homogenized using a roller mixer.Protein formulation preparation

[0545] TA99 formulations were prepared by incorporating a spray dried protein cake directly into a polymeric vehicle prepared by solubilizing copolymers in tripropionin.

[0546] Trehalose, Tween® 80 and L-methionine were added to the commercial TA99 solution so as to achieve about 15 to 30% (w / w) antibody content in the final powder preparation.

[0547] The TA99 protein solution containing trehalose, Tween® 80 and L-methionine was filtered on a 0.2 pm regenerated cellulose filter prior to the spray drying process. Spray drying was performed using a B-290 mini spray dryer from Buchi (Switzerland). Operating conditions were set as follows: inlet temperature of 85°C, flow rate of 1 .5 mL / min, aspirator rate at 100% and air flow varying between 600-1000 L / h. The observed outlet temperature during the run was between 57 and 60°C. Protein powder was collected into a sterile glass vial and was further dried overnight in vacuum oven before storage at 4°C. The protein content was assessed by SEC-HPLC. Trehalose content can be measured using an enzymatic kit provided by Libios (Vindry-sur-Turdine, France).Example 3: In vitro release (IVR) tests

[0548] The release profiles of different long-acting formulations were evaluated in vitro.

[0549] Briefly for Imiquimod formulations, depots were formed following the injection of 50 mg of test formulation into 15 mL of sodium acetate pH 5.6 buffer containing 150 mM of NaCI and 0.002% NaN3. Exact masses of formulation injected were recorded and vials were placed at 37°C under constant shaking. At pre-determined time intervals, samples of the IVR medium were collected and analysed by LIPLC. Remaining IVR medium were discarded, and 15 mL of fresh buffer were then added to each vial.

[0550] For Trametinib formulations, same protocol was fallowed except that the IVR buffer was PBS-1X + 2% Tween 80 and the buffer volume was set at 10 mL.

[0551] The compositions of some of the tested formulations are detailed in Table 1.TABLE 1

[0552] Results of the IVR tests are presented in Figures 2 and 3 for imiquimod and trametinib respectively. Data show that depending on the formulation composition sustained release for at least 1 week can be obtained with both imiquimod and trametinib. The high cumulative results obtained with F10-Tram may be explained by the low content of API that may have led to a high variance in weighing.Example 4: Long-acting formulations - pharmacokinetic and local toxicity evaluation

[0553] Following the first IVR tests, different long-acting formulations were selected for evaluation in vivo.

[0554] Briefly, C57BL / 6 mice were injected subcutaneously at study start with around 50 pL of candidate formulation using a syringe equipped with a 25G or 23G needle. On the day of injection (tO) animals were identified and randomized into groups of 8 to 12 animals.

[0555] The compositions of the tested formulations and details of the studies are disclosed in Table 2.TABLE 2

[0556] At each time point, 3 or 4 mice per group were sacrificed to evaluate the remaining API content in the depot and assess the local toxicity. Animals were euthanized and explants were recovered. Remaining depots were dissolved in 1 mL of acetonitrile for explants with trametinib or 1 mL of acetonitrile / H2O (80:20) for explants with imiquimod. After solubilization, solutions were filtered and filtered samples were analyzed by LIPLC.

[0557] Results are disclosed in Table 3 and Figure 4. Table 3 presents the mean % of API retrieved at the latest timepoint of the corresponding study.

[0558] For each formulation detailed in Table 2, a quantifiable amount of API was measured at each time-point in at least one explant, demonstrating the capacity of the long-actingformulations to locally retain the API, e.g. for up to 20 days for trametinib and up to 30 days for imiquimod. No acute or chronic toxicity was observed in mice in terms of weight variation or skin irritation.TABLE 3Example 5: lmiquimod / TA99 pharmacodynamic study

[0559] The effect of combining TA99 with imiquimod was evaluated in a pharmacodynamic study. At study start C56BL / 6 mice were subcutaneously injected on the right flank with 100 pL of B16F10 cells suspended in PBS (ca. 5x104tumor cells).

[0560] Two days post graft, mice were randomized into groups of 12 animals and treated as follows:• Group 1 was the negative control group for which no treatment was provided;• Group 2 was the positive control group and was treated according to the protocol described in They et al. (“PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody”Oncoimmunology (2017)). Briefly, at 2-, 3-, 4-, 7-, 9- and 11-days following tumor graft, 100 pL of a TA99 solution at 2 mg / mL in PBS were injected intraperitoneally;• Group 3 received in the morning of day 2 a peritumoral injection of 50 pL of formulation F20-lm, followed in the afternoon by a first TA99 IP (intraperitoneal) injection and further TA99 IP injections at days 3, 4, 7, 9 and 11 ;• Group 4 received on day 2 a peritumoral injection of 50 pL of formulation F20-lm.

[0561] Formulation F20-lm was prepared as disclosed in Example 2. Its composition is detailed in Table 2.

[0562] Tumor growth was evaluated by measuring tumors 3 times per week with a caliper. Volumes were calculated by using the formula length*width*width / 2. When the tumors reached a volume of 1500 - 1800 mm3, mice were euthanized and survival rate was computed therefrom.

[0563] Results are shown in Figures 5 and 6.

[0564] The study demonstrated that combination therapy of TA99 and imiquimod formulation has a superior therapeutic effect on survival rate and tumor growth control as compared to TA99 mono therapy or imiquimod mono therapy. Treatment with imiquimod F20-lm formulation alone had only a minor impact on delaying the tumor growth and increasing the survival time, compared to the control group.

[0565] 63 days following tumor cells graft, a challenge was performed by further inoculating 5x104B16F10 cells on the opposite flank of surviving mice, which had not developed a tumor by this time. At that time groups 2 and 3 were composed of 3 and 5 animals respectively. A new control group composed of 5 naive animals was simultaneously included in the study. Tumor growth and survival rate were further evaluated as described above.

[0566] Results are shown in Figure 7.

[0567] During the tumor challenge study, tumor appearance was significantly delayed in groups treated previously with TA99 monotherapy or combination therapy previously as compared to the naive mice group, demonstrating a memory immune protection and thereby leading to an increased survival time.

[0568] A pharmacodynamic study was further launched to evaluate the effect of a single peritumoral administration of a formulation comprising TA99 compared to repeated intraperitoneal administrations of TA99 solutions.

[0569] Formulation F2-TA99 was prepared as disclosed in Example 2 by dispersing about 9% TA99 spray-dried cake, corresponding to a final TA99 loading of 1.6%, in a tripropionin based vehicle containing 80% of a 3-arm branched copolymer comprising a PEG core and polyester arms.

[0570] Mice were grafted with B16F10 tumor cells as disclosed in Example 4. Two days following tumor graft, animals were identified and randomized into 4 groups of 12 animals and injected with the following treatments:• Group 1 was the negative control group and did not receive any treatment;• Group 2 was the positive control group and was treated according to the protocol described in They et al. (“PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody” Oncoimmunology (2017)). Briefly, at 2-, 3-, 4-, 7-, 9- and 11-days following tumor graft, 100 pL of a TA99 solution at 2 mg / mL in PBS were injected intraperitoneally;• Group 3 was the test group and received a single peritumoral dose of 60 pL of formulation F2-TA99 using a 250 pL Hamilton syringe 2 days after tumor graft;• Group 4 was the control group and was treated as Group 3 but with the injection of the polymeric vehicle used for F2-TA99 preparation.

[0571] Groups 2 and 3 received an equivalent total amount of TA99 of 1.1 to 1.2 mg.

[0572] Tumor growth and survival rate were evaluated as disclosed in Example 5. Retro-orbital blood samples were withdrawn in mice of groups 2 and 3 at days 15 and 28 post tumor graft and the serum concentration of TA99 was measured using an in-house ELISA test.

[0573] Results are presented in Figures 8 to 10.

[0574] This study demonstrated that a single peritumoral injection of the F2-TA99 formulation achieved the same therapeutic effect in terms of controlling tumor growth and survival rate as compared to 6 peritoneal injections of a TA99 saline solution.

[0575] A similar study as described in Example 5 was performed.

[0576] When tumors reached a volume of 300-400 mm3, mice were euthanized and spleen, draining lymph nodes and tumors recovered and dissociated. Cells were then suspended in PBS containing 1% BSA and were stained with a complete immune cell phenotyping panel composed of 15 labelled monoclonal antibodies (CD45-BV785, CD4-BUV496), CD8a-AF700, Ly-6G-BV605, CD11cBV421, MHC2-BUV395, B220-BV650, NKP46-BUV661 , Foxp3-APC, CD11b-FITC, and F4 / 80-Pe-Vio770, PDL1-PEDazzle, PD1-APCCy7, CD103-BV510, TCRgd- PerCPCy5.5, CD3-PE). After staining, samples were washed, fixed in 1% PFA, and processed for data acquisition using a CytoFLEX S flow cytometer (Beckman Coulter). Data were analyzed using FlowJo v10 software.

[0577] Tumor immune infiltration was evaluated quantitatively and qualitatively depending on the treatment and compared to the immune cell population in peripheral organs (lymph nodes and spleen). Results showed that more effector CD8+ T cells infiltrated into tumors in the combination group 3. These CD8+ T cells were in the active state as demonstrated by the cells being positive for CD103 expression. A lower PD-1 expression further demonstrated the nonexhausted state of these T cells.ic studv of imiquimod formulations

[0578] A further pharmacodynamic study was launched to evaluate the anti-tumor effect of daily topical administration of imiquimod cream alone or in combination with TA99 intraperitoneal injections compared to the TA99 intraperitoneal injections and the single peritumoral injection of a long-acting formulation of imiquimod alone or in combination.

[0579] The protocol described in Example 5 was repeated and 2 further groups were added:

[0580] Group 5 received once daily over 3 weeks a topical administration of ALDARA® 5% (imiquimod cream). The cream was applied with a cotton bud enough to masse on the tumors or tumor inoculation sites.

[0581] Group 6 received once daily over 3 weeks a topical administration of ALDARA® 5% (imiquimod cream) as described in group 5 and one intraperitoneal injection of 100 pL of TA99 solution in PBS (2 mg / mL) at 2-, 3-, 4-, 7-, 9- and 11-days following tumor graft.

[0582] Each group was composed of ca. 10 animals.

[0583] Tumor growth and survival rate was evaluated as detailed in Example 5. Retro-orbital blood samples were withdrawn in 5 mice of groups 4 and 5 at days 2, 7, 14, 21 and 28 post tumor graft on survival mice and the serum concentration of imiquimod was measured in centrifugated samples using a LC-MS / MS method with a LLOPQ of 1 ng / mL.

[0584] Results are disclosed on Figures 11 to 13 and seems to suggest that a single peritumoral injection of imiquimod provides at least the same effect as daily topical administration of imiquimod cream. However, the combination therapy of TA99 and imiquimod long-acting formulation (group 3) has a superior therapeutic effect on survival rate and tumor growth control as compared to TA99 mono therapy (group 2), imiquimod mono therapy (SC or topical administration, group 4 and 5 respectively), or to the combination of TA99 and imiquimiod topical cream (group 6). Moreover, quantification of imiquimod in blood samples showed consistently a higher systemic concentration of imiquimod in animals having been topically administered Imiquimod, highlighting potential long-term issues.Example 9: Influence of the administration site

[0585] A pharmacodynamic study was launched to evaluate the effect of the injection site of an imiquimod long-acting formulation on tumor growth and survival rate.

[0586] Mice were grafted on the right flank with B16F10 cells following the protocol described in Example 5. Two days post tumor graft, 50 pL of formulation F20-lm was administered either by subcutaneous injection in the right flank next to the tumor site (ie by peritumoral injection) (group 1 ; N=12) or by subcutaneous injection in the left flank (group 2; N=12).

[0587] Tumor growth and survival rate were evaluated as detailed in example 5. Results are disclosed in Figure 14 and suggest an initial similar survival rate after subcutaneous injection of F20-lm in the left or the right flank. After 60 days post-graft, an increased survival was observed in the group injected the long-acting formulation on the left flank.ic

[0588] The effect of combining TA99 with a combination of dabrafenib and trametinib, administered either orally or subcutaneously as a long-acting formulation, was further evaluated on mice grafted with NRASmut melanoma cells.

[0589] NRASmut cells obtained from one of the laboratories of the Institut de Recherche de Cancerologie de Montpellier, were selected to mimic mutated melanoma activating the MAPK signalling pathways (NRAS mutated melanoma). In contrast to YLIMM BRAF mutated cells, commonly used in the literature, NRASmut cells have been found to express TYRP1 antigen at the cell surface (data not shown).

[0590] Briefly, cells were maintained in DMEM / F12 with 10% FVS and 1% L-glutamine and prepared for injection by reconstitution in PBS at a concentration of 1*107cells / mL.

[0591] 100 pL of resuspended cells (ca. 1x106cells) were subcutaneously injected in the right flank of mice

[0592] 2 days post graft, mice were randomized into 6 groups and treated as follow:• Group 1 was the control group and received no treatment (n=10);• Group 2 received 6 TA99 IP injections at days 2, 3, 4, 7, 9 and 11 (n= 10) ;• Group 3 received in the morning of day 2 the first peritumoral injection of TA99, followed in the afternoon by one subcutaneous injection of 50pL of a formulation containing dabrafenib and trametinib (F1-Dab / Tram), and further TA99 IP injections at days 3, 4, 7, 9 and 11 (n=10);• Group 4 received one subcutaneous injection of 50 pL of the F1-Dab / Tram formulation (n=19);• Group 5 received 6 TA99 IP injections at days 2, 3, 4, 7, 9 and 11 and was fed daily with Dab / Tram (n=10 ) over 3 weeks. The total oral feeding doses were equivalent to the drug dose found in the F1-Dab / Tram.• Group 6 was fed daily with Dab / Tram (n=10 ) over 3 weeks. The total oral feeding doses were equivalent to the drug dose found in the F1 -Dab / Tram.

[0593] Formulation F1 -Dab / Tram was prepared as disclosed in Example 2 by mixing the polymeric vehicle with the pre-weighed API powders. The resulting formulation contained 14.6% dabrafenib, 0.3% trametinib, 10.6% P2R2, 10.6% dP2R2.4 and 63.8% DMSO.

[0594] At 3, 10 and 25 days after treatment start, 3 mice of group 4 were euthanized and explants recovered. Remaining APIs were extracted from depots and dissolved in 1 mL ACN / H2O (80 / 20) for API quantification.

[0595] Tumor growth and survival rate were evaluated as detailed in example 5. With this cell line, the tumor growth was less aggressive and delayed compared to results obtained inprevious examples with the B16F10 cells. Results over 110 days are presented in Figure 15. In control group 1 , 2 mice out of 10 were euthanized once the tumor had reached the maximum size of 1500 mm3and 8 mice were euthanized due to cachexia (body weight loss of more than 20%). In test group 2, 9 mice were euthanized for cachexia. In test group 3, 4 mice were euthanized because of cachexia and one mouse was euthanized for necrosis at the injection site due to a manipulation mistake. In test group 4, 6 mice were euthanized for cachexia and one mouse was euthanized once the tumor had reached the maximum size of 1500 mm3. In group 5, 7 mice were euthanized for cachexia and one mouse was euthanized once the tumor had reached the maximum size of 1500 mm3. In group 6, 7 mice were euthanized for cachexia and two mouse was euthanized once the tumor had reached the maximum size of 1500 mm3and one mouse was euthanized because of a manipulation mistake (tumor was grafted intraperitoneally). This highlights better survival of mice treated with the combination therapy including the long-acting formulation, despite similar results being obtained with the groups administered dabrafenib / trametinib alone either orally or subcutaneasouly.

[0596] Results from the API quantification are presented in Figure 16 and demonstrate a sustained release of both dabrafenib and trametinib over a period of at least 28 days.Example 11 : imiquimod / anti-PD-1 pharmacodynamic study

[0597] The effect of combining imiquimod with an anti-mouse PD-1 (CD279) antibody (e.g. anti-mouse PD-1 [#BE0146] from BioXcell, Lebanon, New Hampshire, USA) will be evaluated in a pharmacodynamic study using MC38 colorectal tumor cell line. At study start C56BL / 6 mice will be subcutaneously injected on the right flank with around 100 pL of MC38 cells suspended in PBS (ca. 1x106tumor cells).

[0598] Two days post graft, mice will be randomized into groups of 12 animals and treated as follows:• Group 1 will be the negative control group for which no treatment will be provided;• Group 2 will be the positive control group and will be treated with anti-PD-1 antibody only. Briefly, a few days after grafting and once the tumor has reached a sufficient size, mice will receive a first injection of around 100 pL of the mAb solution at 2 mg / mL, injected intraperitoneally followed by subsequent injections at different timepoints• Group 3 will receive in the morning of day 4 a peritumoral injection of 50 pL of formulation F20-lm, followed in the afternoon by the first IP (intraperitoneal) injection ofanti-PD-1 antibody and further antibody IP injections at the same timepoints as group 2• Group 4 will receive on day 4 a peritumoral injection of 50 L of formulation F20-lm.• Group 5 will receive an intra-tumoral injection of 20 L of formulation F20-lm at tumor emergence (30 to 50 mm3tumor volume).

[0599] Formulation F20-lm will be prepared as disclosed in Example 2. Its composition is detailed in Table 3.

[0600] Tumor growth and survival rate will be evaluated as detailed in example 5.Example 12: Immunophenotypinq study

[0601] The study was made of 4 groups containing 5 mice in each group:• Group 1 was the negative control group for which no treatment was provided;• Group 2 received TA99 (intraperitoneal)• Group 3 received a long-acting formulation of imiquimod (peri-tumoral injection)• Group 4 received TA99 (intraperitoneal) and a long-acting formulation of imiquimod (peri-tumoral injection)

[0602] At day 0 of the study, B16F10 cells were injected subcutaneously on the right flank. When the tumors reached around 50 to 100 mm3, the corresponding treatments were initiated, as described in example 5. Ten days after initiation of treatment, all mice were sacrificed at the same time. Tumor, spleen and draining lymphatic nodes were recovered. A phenotyping study was then performed on all samples to determine immune cell populations, and cytokine and chemokine production in tumors.

[0603] It was found that there were more immune cells (T cells, B cells dendritic cells and etc) present in the draining lymph node (inguinal) in the group treated with combination therapy including the long-acting formulation than any monotherapies. This demonstrated a superior recruitement of immune cells to the local lymph node and potentially a better anti-tumor immunity later on.Example 13: Determination of melanocytic antigens level in NRAS mutated cell line

[0604] A study was launched to evaluate the impact of dabrafenib, trametinib or the combination thereof on melanocytic antigens expression on NRAS mutated cell line. Briefly, the NRASmut cells were seeded in petri-dishes at 1x106cells / mL and were treated over 48h with dabrafenib and / or trametinib at a fixed concentration corresponding to their respective IC50. The cells were then harvested and the melanocytic antigens levels were measured through qPCR and FACs.

[0605] Increased melanocytic antigens were measured upon treatment with the combination of dabrafenib and trametinib compared to control or the monotherapies. In particular, a significantly higher TYRP1 (target of the TA99 mAb) expression was measured on treated NRASmut cells, supporting the use of a triple combination therapy including TA99 and a long- acting formulation containing both dabrafenib and trametinib.NUMBERED CLAUSES1. A combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.2. The combination according to clause 1 , wherein at least the second composition comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A),wherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.3. The combination according to clause 1 or clause 2, wherein each of the first and second composition independently comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.4. The combination according to any preceding clause, wherein the at least one antineoplastic antibody or antigen-binding fragment thereof binds to a tumor antigen.5. The combination according to clause 4, wherein the antibody comprises at least one anti-tyrosinase-related protein 1 (TYRP1) antibody or antigen-binding fragment thereof.6. The combination according to clause 4 or clause 5, wherein the antineoplastic antibody or antigen-binding fragment thereof is flanvotumab or an antigen-binding fragment thereof, preferably flanvotumab.7. The combination according to any one of clauses 1 to 3, wherein the at least one antineoplastic antibody comprises at least one immunomodulatory antibody.8. The combination according to clause 7 wherein the immunomodulatory antibody is an immune checkpoint inhibitor.9. The combination according to clause 8, wherein the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof that bind programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and / or ligands thereof.10. The combination according to clause 8 or clause 9, wherein the immune checkpoint inhibitor is an anti-PD-1 or anti-programmed death-ligand 1 (anti-PD-L1) antibody or antigen-binding fragment thereof.11. The combination according to clause 10, wherein the anti-PD-1 , anti-PD-L1 antibody or antigen-binding fragment thereof is selected from nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab, and antigen-binding fragments thereof.12. The combination according to clause 8 or clause 9, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody or antigen-binding fragment thereof.13. The combination according to clause 12, wherein the anti-CTLA-4 antibody or antigenbinding fragment thereof is selected from ipilimumab and antigen-binding fragments thereof.14. The combination according to any preceding clause, wherein the at least one smallmolecule antineoplastic agent is selected from immune response modifiers, protein kinase inhibitors, and combinations thereof.15. The combination according to clause 14, wherein the at least one small-molecule antineoplastic agent is an immune response modifier and comprises a toll-like receptor (TLR) agonist, preferably wherein the TLR agonist is a TLR-7, TLR-8, or TLR-7 / 8 agonist.16. The combination according to clause 15, wherein the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.17. The combination according to clause 14, wherein the at least one small-molecule antineoplastic agent comprises a protein kinase inhibitor.18. The combination according to clause 17, wherein the at least one small-molecule antineoplastic agent comprises an inhibitor of at least one component of the MAPKsignalling pathway, preferably wherein the at least one small-molecule antineoplastic agent comprises an inhibitor of MEK, RAF and / or RAS. The combination according to clause 18, wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting BRAF selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof. The combination according to clause 18, wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting MEK selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof. The combination according to clause 18, wherein the small-molecule antineoplastic agent comprises a first protein kinase inhibitor as defined in clause 19 and a second protein kinase inhibitor as defined in clause 20. The combination according to any preceding clause, wherein the combination comprises a third composition comprising at least one further antineoplastic antibody or antigen-binding fragment thereof and / or small-molecule antineoplastic agent different from each of the antineoplastic antibody or antigen-binding fragment thereof of the first composition and the small-molecule antineoplastic agent of the second composition. The combination according to clause 22, wherein the third composition comprises an antineoplastic antibody or antigen-binding fragment thereof different from the antineoplastic antibody or antigen-binding fragment thereof of the first composition. The combination according to clause 23, wherein the antineoplastic antibody or antigen-binding fragment thereof of the first composition is an anti-PD-1 or anti-PD-1 antibody or antigen-binding fragment thereof as defined in clause 11 , and the antineoplastic antibody or antigen-binding fragment thereof of the third composition is an anti-CTLA-4 antibody or antigen-binding fragment thereof as defined in clause 13. The combination according to any of clauses 1 to 22, wherein the first composition and / or second composition further comprising (c) and (d) is an injectable composition.26. The combination according to clause 25, wherein the injectable composition is liquid at room temperature and forms a semi solid or solid implant when injected into an aqueous environment.27. The combination according to any preceding clause, wherein the at least one polyetherpolyester copolymer (c) is selected from;(i) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units;(iii) a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and(iv) a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;(v) or any combination thereof.28. The combination according to any preceding clause, wherein the polyester of the polyether-polyester copolymer (c) comprises lactic repeat units.29. The combination according to clause 28, wherein the polyester of the polyether- polyester copolymer (c) is poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s-caprolactone-co-lactic acid) (PCLA).30. The combination according to any preceding clause, wherein the end-capped polyethylene glycol is methoxy-polyethylene glycol.The combination according to any preceding clause, wherein the polyester of the polyether-polyester copolymer (c) is poly(D,L-lactic acid) (PLA). The combination according to any preceding clause, wherein the polyether-polyester copolymer (c) is a multi-arm copolymer i) having a molar ratio of the ester repeat unit to the ethylene oxide repeat unit of from 0.5 to 25, preferably from 1 to 10, more preferably from 2 to 6. The combination according to any preceding clause, wherein if the polyether-polyester copolymer (c) is a multi-arm copolymer i) the central core is a multi-arm polyether which is obtainable from PEG and a polyol. The combination according to clause 33, wherein the polyol comprises at least three hydroxyl groups, optionally wherein the polyol is a hydrocarbon substituted with at least three hydroxyl groups, optionally 3 to 8 hydroxyl groups. The combination according to clause 33 or clause 34, wherein the polyol is pentaerythritol (PE), dipentaerythritol, trimethylolpropane (TMP), glycerol, erythritol, xylitol, di(trimethylolpropane (diTMP) sorbitol, or inositol. The combination according to any one of clauses 33 to 35, wherein the polyol further comprises one or more ether groups. The combination according to any one of clauses 1 to 32, wherein the at least one polyether-polyester copolymer (c) is a mixture of a triblock copolymer ii) and a diblock copolymer iii). The combination according to any one of clauses 1 to 32 and 37, wherein the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the triblock copolymer ii) is from 0.5 to 22, preferably from 0.5 to 10, most preferably from 1 to 6. The combination according to any one of clauses 1 to 32, 37, and 38, wherein the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the diblock copolymer iii) is from 0.8 to 15, preferably from 1 to 10, most preferably 1 to 4.The combination according to any preceding clause, wherein the polyether-polyester copolymer is present in the second composition in an amount of from about 10 to about 75 wt% based on the second composition, preferably from about 10 to about 40 wt% based on the second composition. The combination according to any preceding clause, wherein the polyether-polyester copolymer is present in the first composition in an amount of from about 10 to about 40 wt% based on the first composition, preferably from about 10 to about 30 wt% based on the first composition. The combination according to any preceding clause, wherein the small-molecule antineoplastic agent is present in the second composition in an amount of from about 0.2 to about 30 wt% based on the second composition, preferably from about 0.2 to about 10 wt% based on the second composition. The combination according to any preceding clause, wherein the antineoplastic antibody or antigen-binding fragment thereof is present in the first composition in an amount of from about 0.2 to about 20 wt% based on the first composition, preferably from about 0.2 to about 10 wt% based on the first composition. The combination according to any preceding clause, wherein the organic solvent is present in the second composition in an amount of from about 15 to about 85 wt% based on the second composition, preferably from about 40 to about 75 wt% based on the second composition, more preferably from about 50 to about 85 wt% based on the second composition. The combination according to any preceding clause, wherein the organic solvent is present in the first composition in an amount of from about 15 to about 85 wt% based on the first composition, preferably from about 40 to about 75 wt% based on the first composition, more preferably from about 50 to about 85 wt% based on the first composition. The combination according to any preceding clause, wherein the organic solvent is selected from benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methylethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, triacetin, tributyrin, tripropionin, glycofurol or mixtures thereof; preferably wherein the organic solvent is DMSO, NMP, triacetin or tripropionin.47. The combination according to any preceding clause, for use in treating a solid tumor in a subject.48. The combination for use according to clause 47, wherein the tumor is negative for mutations in each of BRAF, KIT, and NRAS.49. The combination for use according to clause 48, wherein the small-molecule antineoplastic agent comprises a TLR agonist; preferably wherein the TLR agonist is a TLR-7, TLR-8, or TLR-7 / 8 agonist; more preferably wherein the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.50. The combination for use according to clause 47, wherein the tumor comprises at least one BRAF, NRAS, MEK, KIT, CTTNB1 , GNA11 , and / or GNAQ mutation, more preferably wherein the tumor comprises at least one BRAF and / or MEK mutation, even more preferably at least one BRAF mutation.51. The combination for use according to clause 50, wherein the tumor comprises at least one BRAF V600 mutation.52. The combination for use according to clause 50 or clause 51 , wherein the smallmolecule antineoplastic agent is a protein kinase inhibitor inhibiting BRAF selected from dabrafenib, encorafenib, trametinib, cobimetinib, binimetinib, pharmaceutically acceptable derivatives thereof, and combinations thereof.53. The combination for use according to clause 50 or clause 51 , wherein the smallmolecule antineoplastic agent is a protein kinase inhibitor inhibiting MEK selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof.54. The combination for use according to clause 50 or clause 51 , wherein the smallmolecule antineoplastic agent is a protein kinase inhibitor selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.55. The combination for use according to clause 50 or clause 51 , wherein the smallmolecule antineoplastic agent comprises a first protein kinase inhibitor as defined by clause 53 and a second protein kinase inhibitor as defined by clause 54.56. The combination for use according to any one of clauses 47 to 55, wherein the tumor is a melanoma, preferably wherein the melanoma is an advanced stage melanoma.57. The combination for use according to any one of clauses 47 to 56, wherein the first and second compositions are simultaneously, separately, or sequentially administered to the subject.58. The combination for use according to any one of clauses 47 to 57, wherein the injectable composition(s) is / are administered by subcutaneous, peri-tumoral or intra- tumoral injection; preferably by peri-tumoral injection.59. A pharmaceutical composition comprising:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.60. The pharmaceutical composition according to clause 59 wherein the at least one antineoplastic antibody or antigen-binding fragment thereof is selected from antibodies or antigen-binding fragments thereof that bind tyrosinase-related protein 1 , programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or ligands thereof.61. A pharmaceutical composition comprising:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent.62. The pharmaceutical composition according to clause 60 wherein the at least one small molecule antineoplastic agent is selected from protein kinase inhibitors, toll-like receptor (TLR) agonists, and combinations thereof.63. The pharmaceutical composition according to clause 61 or clause 62 wherein the smallmolecule antineoplastic agent comprises a first protein kinase inhibitor as defined by clause 53 and a second protein kinase inhibitor as defined by clause 54.64. A method of treating a solid tumor in a subject, the method comprising administering to the subject:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.65. The method according to clause 64, wherein the first composition and the second composition are administered separately, sequentially or simultaneously to the subject.66. A product comprising a combination of:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; as a combined preparation for simultaneous, separate or sequential use in treating a tumor; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.67. A kit comprising:(A) a prefilled syringe comprising a first injectable composition, wherein the injectable composition comprises:- at least one antineoplastic antibody or an antigen-binding fragment thereof, or at least one small-molecule antineoplastic agent;- at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.(B) at least one needle; and(C) instructions for use.68. The kit according to clause 67, wherein the first injectable composition comprises at least one antineoplastic antibody, and the kit further comprises (D) a second composition comprising at least one small-molecule antineoplastic agent.69. The kit according to clause 67, wherein the first injectable composition comprises at least one small-molecule antineoplastic agent, and the kit further comprises (D) a second composition comprising at least one antineoplastic antibody.70. The kit according to clause 68 or clause 69, wherein the second composition is comprised in a prefilled syringe and said second composition is an injectable composition further comprising: at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.71. The kit according to clause 69, wherein the second composition is comprised in a prefilled syringe and said second composition is an injectable aqueous composition comprising: at least one buffer; and optionally at least one pharmaceutically acceptable excipient.72. The pharmaceutical composition according to any one of clauses 59 to 63, the method according to clause 64 or 65, the product for use according to clause 66, or the kit according to any one of clauses 67 to 71 , wherein the at least one polyether-polyester copolymer (ii) is as defined in any one of clauses 27 to 41 , and / or wherein the organic solvent (iii) is as defined in any one of clauses 44 to 46.

Claims

CLAIMS1. A combination comprising:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

2. The combination according to claim 1, wherein at least the second composition comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent; optionally wherein each of the first and second composition independently comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

3. The combination according to any preceding claim, wherein the at least one antineoplastic antibody or antigen-binding fragment thereof binds to a tumor antigen; optionally wherein the antibody comprises at least one anti-tyrosinase-related protein 1 (TYRP1) antibody or antigen-binding fragment thereof.

4. The combination according to claim 3, wherein the antineoplastic antibody or antigenbinding fragment thereof is flanvotumab or an antigen-binding fragment thereof, preferably flanvotumab.

5. The combination according to claim 1 or 2, wherein the at least one antineoplastic antibody comprises at least one immunomodulatory antibody; optionally wherein the immunomodulatory antibody is an immune checkpoint inhibitor; optionally wherein the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof that bind programmed cell death protein 1 (PD- 1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and / or ligands thereof.

6. The combination according to claim 5, wherein the immunomodulatory antibody is an immune checkpoint inhibitor that is an anti-PD-1 or anti-programmed death-ligand 1 (anti-PD-L1) antibody or antigen-binding fragment thereof; optionally wherein the anti-PD-1, anti-PD-L1 antibody or antigen-binding fragment thereof is selected from nivolumab, pembrolizumab, atezolizumab, cemiplimab, avelumab, durvalumab, tislelizumab, sintilimab, and antigen-binding fragments thereof.

7. The combination according to claim 5, wherein the immunomodulatory antibody is an immune checkpoint inhibitor that is an anti-CTLA-4 antibody or antigen-binding fragment thereof; optionally wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is selected from ipilimumab and antigen-binding fragments thereof.

8. The combination according to any preceding claim, wherein the at least one smallmolecule antineoplastic agent is selected from immune response modifiers, protein kinase inhibitors, and combinations thereof;optionally wherein the at least one small-molecule antineoplastic agent is an immune response modifier and comprises a toll-like receptor (TLR) agonist, preferably wherein the TLR agonist is a TLR-7, TLR-8, or TLR-7 / 8 agonist; more preferably wherein the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

9. The combination according to claim 8, wherein the at least one small-molecule antineoplastic agent comprises a protein kinase inhibitor; optionally wherein the at least one small-molecule antineoplastic agent comprises an inhibitor of at least one component of the MAPK signalling pathway, preferably wherein the at least one small-molecule antineoplastic agent comprises an inhibitor of MEK, RAF and / or RAS.

10. The combination according to claim 9, wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting BRAF selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof; or wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting MEK selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

11. The combination according to claim 9, wherein the small-molecule antineoplastic agent comprises a first protein kinase inhibitor inhibiting BRAF selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor inhibiting MEK selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

12. The combination according to any preceding claim, wherein the combination comprises a third composition comprising at least one further antineoplastic antibody or antigenbinding fragment thereof and / or small-molecule antineoplastic agent different from each of the antineoplastic antibody or antigen-binding fragment thereof of the first composition and the small-molecule antineoplastic agent of the second composition; optionally wherein the third composition comprises an antineoplastic antibody or antigen-binding fragment thereof different from the antineoplastic antibody or antigen-binding fragment thereof of the first composition;optionally wherein the antineoplastic antibody or antigen-binding fragment thereof of the first composition is an anti-PD-1 or anti-PD-1 antibody or antigen-binding fragment thereof as defined in claim 6, and the antineoplastic antibody or antigenbinding fragment thereof of the third composition is an anti-CTLA-4 antibody or antigenbinding fragment thereof as defined in claim 7.

13. The combination according to any of claims 1 to 12, wherein the first composition and / or second composition further comprising (c) and (d) is an injectable composition; optionally wherein the injectable composition is liquid at room temperature and forms a semi solid or solid implant when injected into an aqueous environment.

14. The combination according to any preceding claim, wherein the at least one polyetherpolyester copolymer (c) is selected from;(i) a multi-arm copolymer having 3 to 8 polyester arms attached to a central core which is a multi-arm polyether comprising PEG and wherein each polyether arm has from 2 to 150 ethylene oxide repeat units and each polyester arm has from 4 to 200 repeat units;(ii) a triblock copolymer, wherein the triblock copolymer has the formula:Av-Bw-Ax wherein A is a polyester and B is PEG and v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v x; and(iii) a diblock copolymer, wherein the diblock copolymer has the formula:Cy-Az wherein A is a polyester and C is an end-capped PEG and y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000;(iv) or any combination thereof.

15. The combination according to any preceding claim, wherein the polyester of the polyether-polyester copolymer (c) comprises lactic repeat units;optionally wherein the polyester of the polyether-polyester copolymer (c) is poly(D,L-lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) or poly(s- caprolactone-co-lactic acid) (PCLA).

16. The combination according to any preceding claim, wherein the end-capped polyethylene glycol is methoxy-polyethylene glycol.

17. The combination according to any preceding claim, wherein the polyester of the polyether-polyester copolymer (c) is poly(D,L-lactic acid) (PLA).

18. The combination according to any preceding claim, wherein the polyether-polyester copolymer (c) is a multi-arm copolymer i) having a molar ratio of the ester repeat unit to the ethylene oxide repeat unit of from 0.5 to 25, preferably from 1 to 10, more preferably from 2 to 6.

19. The combination according to any preceding claim, wherein if the polyether-polyester copolymer (c) is a multi-arm copolymer i) the central core is a multi-arm polyether which is obtainable from PEG and a polyol; optionally wherein the polyol comprises at least three hydroxyl groups, optionally wherein the polyol is a hydrocarbon substituted with at least three hydroxyl groups, optionally 3 to 8 hydroxyl groups; optionally wherein the polyol is pentaerythritol (PE), dipentaerythritol, trimethylolpropane (TMP), glycerol, erythritol, xylitol, di(trimethylolpropane (diTMP) sorbitol, or inositol; optionally wherein the polyol further comprises one or more ether groups.

20. The combination according to any one of claims 1 to 18, wherein the at least one polyether-polyester copolymer (c) is a mixture of a triblock copolymer ii) and a diblock copolymer iii).

21. The combination according to any one of claims 1 to 18 and 20, wherein the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the triblock copolymer ii) is from 0.5 to 22, preferably from 0.5 to 10, most preferably from 1 to 6; and / or the molar ratio of the ester repeat unit to the ethylene oxide repeat unit for the diblock copolymer iii) is from 0.8 to 15, preferably from 1 to 10, most preferably 1 to 4.

22. The combination according to any preceding claim, wherein the polyether-polyester copolymer is present in the second composition in an amount of from about 10 to about 75 wt% based on the second composition, preferably from about 10 to about 40 wt% based on the second composition; and / or wherein the polyether-polyester copolymer is present in the first composition in an amount of from about 10 to about 40 wt% based on the first composition, preferably from about 10 to about 30 wt% based on the first composition; and / or wherein the small-molecule antineoplastic agent is present in the second composition in an amount of from about 0.2 to about 30 wt% based on the second composition, preferably from about 0.2 to about 10 wt% based on the second composition; and / or wherein the antineoplastic antibody or antigen-binding fragment thereof is present in the first composition in an amount of from about 0.2 to about 20 wt% based on the first composition, preferably from about 0.2 to about 10 wt% based on the first composition; and / or wherein the organic solvent is present in the second composition in an amount of from about 15 to about 85 wt% based on the second composition, preferably from about 40 to about 75 wt% based on the second composition, more preferably from about 50 to about 85 wt% based on the second composition; and / or wherein the organic solvent is present in the first composition in an amount of from about 15 to about 85 wt% based on the first composition, preferably from about 40 to about 75 wt% based on the first composition, more preferably from about 50 to about 85 wt% based on the first composition.

23. The combination according to any preceding claim, wherein the organic solvent is selected from benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, triacetin, tributyrin, tripropionin, glycofurol or mixtures thereof; preferably wherein the organic solvent is DMSO, NMP, triacetin or tripropionin.

24. The combination according to any preceding claim, for use in treating a solid tumor in a subject.

25. The combination for use according to claim 24, wherein the tumor is negative for mutations in each of BRAF, KIT, and NRAS; optionally wherein the small-molecule antineoplastic agent comprises a TLR agonist; preferably wherein the TLR agonist is a TLR-7, TLR-8, or TLR-7 / 8 agonist; more preferably wherein the TLR agonist is selected from imiquimod, resiquimod, motolimod, pharmaceutically acceptable derivatives thereof, and combinations thereof.

26. The combination for use according to claim 24, wherein the tumor comprises at least one BRAF, NRAS, MEK, KIT, CTTNB1 , GNA11 , and / or GNAQ mutation, more preferably wherein the tumor comprises at least one BRAF and / or MEK mutation, even more preferably at least one BRAF mutation; yet more preferably at least one BRAF V600 mutation.

27. The combination for use according to claim 26, wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting BRAF selected from dabrafenib, encorafenib, trametinib, cobimetinib, binimetinib, pharmaceutically acceptable derivatives thereof, and combinations thereof; or wherein the small-molecule antineoplastic agent is a protein kinase inhibitor inhibiting MEK selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof.

28. The combination for use according to claim 26, wherein the small-molecule antineoplastic agent is a protein kinase inhibitor selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof; optionally wherein the small-molecule antineoplastic agent comprises a first protein kinase inhibitor inhibiting MEK selected from dabrafenib, encorafenib, and pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

29. The combination for use according to any one of claims 24 to 28, wherein the tumor is a melanoma, preferably wherein the melanoma is an advanced stage melanoma.

30. The combination for use according to any one of claims 24 to 29, wherein the first and second compositions are simultaneously, separately, or sequentially administered to the subject; optionally wherein the composition(s) is / are administered by subcutaneous, peri-tumoral or intra-tumoral injection; preferably by peri-tumoral injection.

31. A pharmaceutical composition comprising:(i) at least one antineoplastic antibody or an antigen-binding fragment thereof;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent; optionally wherein the at least one antineoplastic antibody or antigen-binding fragment thereof is selected from antibodies or antigen-binding fragments thereof that bind tyrosinase-related protein 1, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or ligands thereof.

32. A pharmaceutical composition comprising:(i) at least one small-molecule antineoplastic agent;(ii) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(iii) an organic solvent; optionally wherein the at least one small molecule antineoplastic agent is selected from protein kinase inhibitors, toll-like receptor (TLR) agonists, and combinations thereof; and / or wherein the small-molecule antineoplastic agent comprises a first protein kinase inhibitor inhibiting MEK selected from dabrafenib, encorafenib,and pharmaceutically acceptable derivatives thereof, and a second protein kinase inhibitor selected from trametinib, cobimetinib, binimetinib, and pharmaceutically acceptable derivatives thereof.

33. A method of treating a solid tumor in a subject, the method comprising administering to the subject:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent; optionally wherein the first composition and the second composition are administered separately, sequentially or simultaneously to the subject.

34. A product comprising a combination of:(a) a first composition comprising at least one antineoplastic antibody or an antigen-binding fragment thereof; and(b) a second composition comprising at least one small-molecule antineoplastic agent; as a combined preparation for simultaneous, separate or sequential use in treating a tumor; wherein at least one of the first composition and the second composition further comprises:(c) at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and(d) at least one organic solvent.

35. A kit comprising:(A) a prefilled syringe comprising a first injectable composition, wherein the injectable composition comprises:- at least one antineoplastic antibody or an antigen-binding fragment thereof, or at least one small-molecule antineoplastic agent;- at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A)nwherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.(B) at least one needle; and(C) instructions for use.

36. The kit according to claim 35, wherein the first injectable composition comprises at least one antineoplastic antibody, and the kit further comprises (D) a second composition comprising at least one small-molecule antineoplastic agent.

37. The kit according to claim 35, wherein the first injectable composition comprises at least one small-molecule antineoplastic agent, and the kit further comprises (D) a second composition comprising at least one antineoplastic antibody.

38. The kit according to claim 36 or claim 37, wherein the second composition is comprised in a prefilled syringe and said second composition is an injectable composition further comprising: at least one polyether-polyester copolymer, wherein the copolymer has the formula:B(A),wherein B represents a polyether and comprises polyethylene glycol (PEG), each A represents a polyester arm and n is an integer from 1 to 8; and at least one organic solvent.

39. The kit according to claim 37, wherein the second composition is comprised in a prefilled syringe and said second composition is an injectable aqueous composition comprising: at least one buffer; and optionally at least one pharmaceutically acceptable excipient.

40. The pharmaceutical composition according to claim 31 or 32, the method according to claim 33, the product for use according to claim 34, or the kit according to any one of claims 35 to 39, wherein the at least one polyether-polyester copolymer (ii) is as defined in any one of claims 14 to 22, and / or wherein the organic solvent (iii) is as defined in claim 22 or 23.

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