Monolithic implantable device for sustained release of antibodies

Abstract

A monomeric implantable device for delivering an antibody is provided. The implantable device comprises a polymer matrix within which is dispersed a pharmaceutical formulation comprising one or more therapeutic agents and optionally one or more excipients. The therapeutic agent contains an antibody, and the polymer matrix contains a hydrophobic polymer. The device exhibits a cumulative weight-based release rate of antibodies of from about 20% to about 60% over a time period of 35 days.

Description

[0001] Related Applications

[0002] This application is based on and claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 351,471, filed on June 13, 2022, and U.S. Provisional Patent Application Serial No. 63 / 358,345, filed on July 5, 2022, which are incorporated herein by reference. Background Art

[0003] Antibodies are typically composed of one or more oligomeric or polymeric chains, forming a three-dimensional structure bound together by non-covalent forces. Although antibodies have the potential for a variety of therapeutic benefits, it is traditionally difficult to controllably deliver these compounds over a sustained period of time. For example, many implantable delivery devices are formed by dispersing drug formulations into matrix polymers. These dispersed drug molecules can diffuse through implants and be released into the patient's body. Unfortunately, however, drug elution is highly dependent on the diffusion coefficient of drug molecules, which typically decreases as the molecular weight of drug molecules increases. Therefore, antibodies tend to have lower diffusion coefficients due to their larger molecular weight. In addition, such compounds typically have chain length entanglements, which can further reduce the effective diffusion coefficient. Various attempts have been made to help improve and control the rate at which certain types of drug compounds are released from implantable devices. For example, U.S. Patent Publication No. 2021 / 0007973 describes a device comprising a shell that is applied to an internal implant and comprises a mixture of a polymer matrix and a hydrophilic porogen (e.g., ethyl cellulose). Unfortunately, the use of such porogen shells does not always result in efficient antibody release, and in any case the additional shell can make the device overly complex and expensive to manufacture.

[0004] In view of these difficulties, there remains a need for an implantable delivery device that can deliver antibodies in effective amounts over a sustained period of time. Summary of the invention

[0005] According to one embodiment of the present invention, a monomeric implantable device for delivering an antibody is disclosed. The implantable device comprises a polymer matrix, in which a pharmaceutical preparation is dispersed, the pharmaceutical preparation comprising one or more therapeutic agents and optionally one or more excipients. The therapeutic agent comprises an antibody, and the polymer matrix comprises a hydrophobic polymer. Over a period of 35 days, the device exhibits a cumulative release rate of the antibody based on weight of about 20% to about 60%.

[0006] Other features and aspects of the invention are described in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] A full and enabling disclosure of the invention including the best mode thereof occurring to one of ordinary skill in the art is more particularly set forth in the remainder of the specification which refers to the accompanying drawings in which:

[0008] Figure 1 A graph showing the relationship between the cumulative release percentage based on weight and the release time (hours) of the IgG antibody pharmaceutical preparations in Examples 1 to 3;

[0009] Figure 2 is a graph showing the relationship between the cumulative surface area release and time in Examples 1 to 3;

[0010] Figure 3 A graph showing the relationship between the cumulative release percentage based on weight and the release time (hours) of the trastuzumab drug preparation in Example 4;

[0011] Figure 4 is a graph showing the relationship between the cumulative release percentage based on weight and the release time (hours) of lysozyme in Examples 5 to 6;

[0012] Figure 5 It is the SEC chromatogram of Example 7;

[0013] Figure 6 It is the SEC chromatogram of Example 8;

[0014] Figure 7 It is the SEC chromatogram of Example 9;

[0015] Figure 8 is the SEC chromatogram of Example 10; and

[0016] Fig. 9 This is the SEC chromatogram of Example 11.

[0017] Repeat use of reference characters in the present specification and drawings is intended to represent the same or analogous features or elements of the invention. DETAILED DESCRIPTION

[0018] Those skilled in the art will appreciate that the current discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the present disclosure.

[0019] In general, the present invention relates to a monomeric implantable device that can deliver antibodies that can prevent and / or treat conditions, diseases and / or cosmetic conditions of patients (e.g., humans, pets, farm animals, etc.). As used herein, the term "monomeric" generally means that the device is formed by a single component layer or element, which is generally referred to as a "core". Therefore, the device generally lacks additional release layers, such as shells, membranes, sheaths, etc., so that the core itself can define the external peripheral surface of the device. The monomeric implantable device comprises a polymer matrix, which includes a hydrophobic polymer and a pharmaceutical preparation dispersed in the polymer matrix. The pharmaceutical preparation includes one or more therapeutic agents comprising antibodies and one or more optional excipients, such as buffers, stabilizers (e.g., surfactants, sugars, etc.), etc.

[0020] The weight ratio of therapeutic agent (such as antibody) to polymer matrix can vary depending on the presence of any optional excipient. For example, when only therapeutic agent is present, the weight ratio of therapeutic agent to polymer matrix is ​​generally controlled within the range of about 0.7 to about 1, in some embodiments about 0.75 to about 1, in some embodiments about 0.75 to about 0.9, and in some embodiments about 0.8 to about 0.85. On the other hand, when excipient is present, the weight ratio of therapeutic agent to polymer matrix can be about 0.3 to about 1, in some embodiments about 0.75 to about 1, in some embodiments about 0.35 to about 0.5, and in some embodiments about 0.38 to about 0.45. In any case, the inventors unexpectedly found that when the weight ratio of the overall drug formulation to the polymer matrix is ​​maintained within the range of about 0.7 to about 1, in some embodiments about 0.75 to about 1, in some embodiments about 0.75 to about 0.9, and in some embodiments about 0.8 to about 0.85, the cumulative release rate of the drug from the device can be controlled within the desired range. For example, the drug formulation may comprise from about 30 wt.% to about 50 wt.%, in some embodiments from about 35 wt.% to about 50 wt.%, in some embodiments from about 40 wt.% to about 50 wt.%, and in some embodiments from about 42 wt.% to about 48 wt.% of the device. Likewise, the polymer matrix may comprise from about 50 wt.% to about 70 wt.%, in some embodiments from about 50 wt.% to about 65 wt.%, in some embodiments from about 50 wt.% to about 60 wt.%, and in some embodiments from about 52 wt.% to about 58 wt.% of the device.

[0021] By selectively controlling the specific properties and concentrations of the components of the implantable device, the inventors have found that the resulting device can effectively release antibodies over a long period of time. For example, the implantable device can release antibodies over a period of about 5 days or longer, about 10 days or longer in some embodiments, about 20 days to about 210 days in some embodiments, and about 30 days to about 180 days in some embodiments. In addition, the inventors have also found that antibodies can be released in a highly controlled manner over the release time period. For example, after a period of 15 days, the cumulative release rate of the antibody based on weight can be about 10% to about 55%, about 12% to about 40% in some embodiments, and about 15% to about 30% in some embodiments. Similarly, after a period of 35 days, the cumulative release rate of the antibody based on weight can be about 20% to about 60%, about 30% to about 55% in some embodiments, and about 35% to about 50% in some embodiments. "Accumulative release rate based on weight" can be determined by dividing the total amount of antibodies released in a specific time interval by the total amount of antibodies initially present, and then multiplying the number by 100. Furthermore, after a period of 35 days, the cumulative release rate based on surface area can be from about 5 to about 70 mg / cm 2 , in some embodiments, from about 10 to about 50 mg / cm 2 , in some embodiments, from about 15 to about 40 mg / cm 2 Likewise, after a period of 90 days, the cumulative release rate based on surface area may be from about 15 to about 70 mg / cm 2 , in some embodiments, from about 20 to about 60 mg / cm 2 , and in some embodiments, from about 30 to about 50 mg / cm 2 In addition, after a period of 120 days, the cumulative release rate based on surface area can be from about 30 to about 70 mg / cm 2 , in some embodiments, from about 35 to about 65 mg / cm 2 , and in some embodiments, from about 40 to about 50 mg / cm 2 The “surface-based cumulative release rate” can be calculated by dividing the amount of antibody released in a specific time interval (“mg”) by the surface area of ​​the implantable device from which the antibody can be released (“cm 2 ”) to determine.

[0022] Various embodiments of the present invention will now be described in further detail.

[0023] I. Polymer Matrix

[0024] As described above, the polymer matrix includes at least one polymer that is generally hydrophobic in nature so that it can maintain its structural integrity for a certain period of time when placed in an aqueous environment (e.g., a mammal's body) and is sufficiently stable to be stored for a long time before use. Examples of suitable hydrophobic polymers for this purpose can include, for example, polysiloxane polymers, polyolefins, polyvinyl chloride, polycarbonates, polysulfones, styrene acrylonitrile copolymers, polyurethanes, polysiloxane polyether-urethanes, polycarbonate-urethanes, polysiloxane polycarbonate-urethanes, and the like and combinations thereof. Of course, hydrophilic polymers coated or otherwise encapsulated with a hydrophobic polymer are considered "hydrophobic polymers" and are also suitable for polymer matrices. The hydrophobic polymer and the resulting polymer matrix may also have a melt flow index ranging from about 0.2 g / 10 min to about 100 g / 10 min, in some embodiments from about 5 g / 10 min to about 90 g / 10 min, in some embodiments from about 10 g / 10 min to about 80 g / 10 min, and in some embodiments from about 30 g / 10 min to about 70 g / 10 min, as measured according to ASTM D1238-20 at a temperature of 190° C. and a load of 2.16 kg. The hydrophobic polymer and the resulting polymer matrix may also have a density ranging from about 0.900 to about 1.00 g / cm 3 (g / cm 3 ), in some embodiments from about 0.910 to about 0.980 g / cm 3 , and in some embodiments, from about 0.940 to about 0.970 g / cm 3 Further, the hydrophobic polymer and resulting polymer matrix may also have a melting temperature range of, for example, from about 40°C to about 140°C, in some embodiments from about 50°C to about 125°C, and in some embodiments from about 60°C to about 120°C, as determined according to ASTM D3418-21.

[0025] In certain embodiments, the polymer matrix may include a semi-crystalline olefin copolymer. Such copolymers are generally derived from at least one olefin monomer (e.g., ethylene, propylene, etc.) and at least one polar monomer grafted to the polymer backbone and / or incorporated as a component of the polymer (e.g., block or random copolymer). Suitable polar monomers include, for example, vinyl acetate, vinyl alcohol, maleic anhydride, maleic acid, (meth) acrylic acid (e.g., acrylic acid, methacrylic acid, etc.), (meth) acrylates (e.g., acrylates, methacrylates, ethyl acrylate, methyl methacrylate, ethyl methacrylate, etc.). Various such copolymers are generally useful in the polymer composition, such as ethylene-vinyl acetate copolymers, ethylene (meth) acrylic acid polymers (e.g., ethylene acrylic acid copolymers and partially neutralized ionic polymers of these copolymers, ethylene methacrylic acid copolymers and partially neutralized ionic polymers of these copolymers, etc.), ethylene (meth) acrylic acid ester polymers (e.g., ethylene methyl acrylate copolymers, ethylene ethyl acrylate copolymers, ethylene butyl acrylate copolymers, etc.). Regardless of the specific monomer selected, certain aspects of the copolymer can be selectively controlled to help achieve desired release properties. For example, the polar monomer content of the copolymer can be selectively controlled in the range of about 10 wt.% to about 60 wt.%, in some embodiments, about 20 wt.% to about 60 wt.%, in some embodiments, about 25 wt.% to about 50 wt.%, in some embodiments, about 30 wt.% to about 48 wt.%, and in some embodiments, about 35 wt.% to about 45 wt.%. Conversely, the olefin monomer content of the copolymer can also range from about 40 wt.% to about 90 wt.%, in some embodiments, about 40 wt.% to about 80 wt.%, in some embodiments, about 50 wt.% to about 75 wt.%, in some embodiments, about 50 wt.% to about 80 wt.%, in some embodiments, about 52 wt.% to about 70 wt.%, and in some embodiments, about 55 wt.% to about 65 wt.%. In addition, such a comonomer content can help achieve controlled, sustained release characteristics of the drug formulation while also having a relatively low melting temperature, which is more similar in nature to the melting temperature of a hydrophobic polymer.

[0026] In one embodiment, for example, the polymer matrix may include at least one ethylene-vinyl acetate polymer, which is a copolymer derived from at least one ethylene monomer (olefin monomer) and at least one vinyl acetate monomer (polar monomer). The melting temperature, monomer content, melt flow index, and / or density may be within the above ranges. Particularly suitable examples of ethylene-vinyl acetate copolymers that can be used include those available from Celanese under the name (For example 4030AC); available from Dow under the name (For example, 40W); and a copolymer obtained from Arkema under the name (e.g., EVATANE 40-55).

[0027] Generally, any of a variety of techniques can be used to form ethylene-vinyl acetate copolymers with desired properties known in the art. In one embodiment, the polymer is prepared by copolymerizing ethylene monomer with vinyl acetate monomer in a high pressure reaction. Vinyl acetate can be prepared by oxidation of butane to produce acetic anhydride and acetaldehyde (which can react together to form diacetylene acetate). Then diacetylene acetate can be thermally decomposed in the presence of an acid catalyst to form vinyl acetate monomer. Examples of suitable acid catalysts include aromatic sulfonic acids (e.g., benzenesulfonic acid, toluenesulfonic acid, ethylbenzenesulfonic acid, xylenesulfonic acid and naphthalenesulfonic acid), sulfuric acid and alkanesulfonic acids, such as those described in U.S. Patent No. 2,425,389 of Oxley et al., U.S. Patent No. 2,859,241 of Schnizer and U.S. Patent No. 4,843,170 of Isshiki et al. Vinyl acetate monomer can also be prepared by reacting acetic anhydride with hydrogen in the presence of a catalyst instead of acetaldehyde. The process directly converts vinyl acetate from acetic anhydride and hydrogen without producing diacetylene acetate. In yet another embodiment, the vinyl acetate monomer may be prepared by reacting acetaldehyde with ketene in the presence of a suitable solid catalyst such as a perfluorosulfonic acid resin or a zeolite.

[0028] In certain embodiments, it may also be desirable to use a blend of a first hydrophobic polymer and a second hydrophobic polymer so that the entire blend and polymer matrix have a melting temperature and / or melt flow index within the above ranges. For example, the polymer matrix may include a first hydrophobic polymer (e.g., ethylene-vinyl acetate copolymer) and a second hydrophobic polymer (e.g., ethylene-vinyl acetate copolymer) having a melting temperature higher than the melting temperature of the first polymer. The second polymer may also have a melt flow index that is the same as, lower than, or higher than the corresponding melt flow index of the first polymer. The first polymer may, for example, have a melting temperature of, for example, from about 20°C to about 60°C, in some embodiments from about 25°C to about 55°C, and in some embodiments from about 30°C to about 50°C, as measured according to ASTM D3418-21, and / or a melt flow index of from about 40 g / 10 min to about 900 g / 10 min, in some embodiments from about 50 g / 10 min to about 500 g / 10 min, and in some embodiments from about 55 g / 10 min to about 250 g / 10 min, as measured according to ASTM D1238-20 at a temperature of 190°C and a load of 2.16 kilograms. The second polymer may also have, for example, a melting temperature of from about 50° C. to about 100° C., in some embodiments from about 55° C. to about 90° C., and in some embodiments from about 60° C. to about 80° C., as measured according to ASTM D3418-21, and / or a melt flow index of from about 0.2 g / 10 min. to about 55 g / 10 min., in some embodiments from about 0.5 g / 10 min. to about 50 g / 10 min., and in some embodiments from about 1 g / 10 min. to about 40 g / 10 min., as measured according to ASTM D1238-20 at a temperature of 190° C. and a load of 2.16 kilograms. The first polymer may constitute from about 20 wt.% to about 80 wt.%, in some embodiments from about 30 wt.% to about 70 wt.%, and in some embodiments from about 40 wt.% to about 60 wt.% of the polymer matrix, and the second polymer may likewise constitute from about 20 wt.% to about 80 wt.%, in some embodiments from about 30 wt.% to about 70 wt.%, and in some embodiments from about 40 wt.% to about 60 wt.% of the polymer matrix.

[0029] Typically, hydrophobic polymers (e.g., ethylene-vinyl acetate copolymers) constitute the entire polymer matrix. In other words, the polymer matrix is ​​generally free of hydrophilic polymers, such as alkyl cellulose and hydroxyalkyl cellulose (e.g., ethyl cellulose, methyl cellulose, and hydroxymethyl cellulose), polyvinyl pyrrolidone, etc. That is, the hydrophilic polymer generally constitutes no more than about 10 wt.%, in some embodiments no more than about 5 wt.%, and in some embodiments constitutes 0 wt.% to about 2 wt.% (e.g., 0 wt.%) of the polymer matrix. For example, ethylene-vinyl acetate copolymers can constitute the entire polymer matrix. In other embodiments, ethylene-vinyl acetate copolymers can be blended with other types of hydrophobic polymers. In such embodiments, the ethylene-vinyl acetate copolymer may constitute from about 70 wt.% to about 99.999 wt.%, in some embodiments from about 80 wt.% to about 99.99 wt.%, and in some embodiments from about 90 wt.% to about 99.9 wt.%, of the polymer content of the polymer matrix, while the other hydrophobic polymer constitutes from about 0.001 wt.% to about 30 wt.%, in some embodiments from about 0.01 wt.% to about 20 wt.%, and in some embodiments from about 0.1 wt.% to about 10 wt.% of the polymer content of the polymer matrix.

[0030] II. Pharmaceutical preparations

[0031] A. Therapeutic agents

[0032] The pharmaceutical preparation is also dispersed in a polymer matrix containing one or more therapeutic agents, including at least one antibody capable of preventing and / or treating a patient's condition, disease and / or cosmetic state. As used herein, the term "antibody (Ab)" generally includes, for example, naturally occurring and non-naturally occurring Ab, monoclonal and polyclonal Ab, chimeric and humanized Ab; human or non-human Ab, fully synthetic Ab, single-chain Ab, etc. Non-human Ab can be humanized by recombinant methods to reduce its immunogenicity in humans. The term "antibody" also includes an antigen-binding fragment or antigen-binding portion of any of the above-mentioned immunoglobulins, and includes monovalent and bivalent fragments or portions, and single-chain Ab. Particularly suitable antibodies may include monoclonal antibodies ("MAbs"), multispecific (e.g., bispecific) antibodies, or combinations thereof. The term "monoclonal antibody" generally refers to a non-naturally occurring preparation of an Ab molecule composed of a single molecule, i.e., an Ab molecule having substantially the same primary sequence, which exhibits a single binding specificity and affinity for a specific epitope. On the other hand, a multispecific antibody can simultaneously bind to different antigens (e.g., two antigens). Such antibodies are usually produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art. "Human" antibody refers to Ab with a variable region of framework region and CDR region derived from human germline immunoglobulin sequence. In addition, if Ab contains a constant region, the constant region is also derived from human germline immunoglobulin sequence. Human Ab may include amino acid residues not encoded by human germline immunoglobulin sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include Abs in which the CDR sequence of the germline derived from another mammalian species (e.g., mouse) is transplanted to a human skeleton sequence.

[0033] In some embodiments, the antibody (including its fragment) can neutralize, block, inhibit, eliminate, reduce and / or interfere with one or more biological activities of proliferating cells (e.g., mitogenic, angiogenic and / or vascular permeability). Such antibodies can, for example, bind to HER 2, TNF-α, VEGF-A, α4-integrin, CD20, CD52, CD25, CD11a, EGFR, respiratory syncytial virus (RSV), glycoprotein IIb / IIIa, IgG1, IgE, complement component 5 (C5), B cell activation factor (BAFF), CD19, CD30, interleukin-1β (IL1β), prostate specific membrane antigen (PSMA), CD38, RANKL, GD2, SLAMF7 (CD319), proprotein convertase subtilisin / kexin PCSK9, dabigatran, cytotoxic T lymphocyte-associated protein 4 (CTLA4), interleukin-5 (IL-5), programmed cell death protein (PD-1), VEGFR2 (KDR), protective antigen (PA) of Bacillus anthracis (B. anthracis), interleukin-17 (IL-17), interleukin-6 (IL-6), interleukin-6 receptor (IL6R), interleukin-12 (IL-12), interleukin 23 (IL-23), sclerosis protein (SOST), myostatin (GDF-8), activin receptor-like kinase 1, delta-like ligand 4 (DLL4), angiopoietin 3, VEGFR1, selectin, oxidized low-density lipoprotein (oxLDL), platelet-derived growth factor receptor β, neuropilin 1, von Willebrand factor (vWF), neuronal apoptosis-regulating protease 1, β-amyloid protein, reticulin 4 (RTN4) / neurite outgrowth inhibitor (NOGO-A), nerve growth factor (NGF), LINGO-1, myelin-associated glycoprotein, etc., and combinations thereof.

[0034] In one embodiment, for example, the antibody can be an anti-PD-1 and / or anti-PD-L1 antibody, for example, used as an immune checkpoint inhibitor for the treatment of cancer. PD-1 (or programmed death-1) refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is mainly expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863. PD-L1 (programmed death protein ligand-1) is one of the two cell surface glycoprotein ligands of PD-1 (the other is PD-L2), and PD-L1 downregulates T cell activation and cytokine secretion after binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank Accession No. Q9NZQ7. HuMAbs that specifically bind to PD-1 with high affinity have been described, for example, in U.S. Pat. Nos. 8,008,449 and 8,779,105. Other anti-PD-1 mAbs have been described, for example, in U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757 and 8,354,509 and PCT Publication No. WO2012 / 145493. For example, an anti-PD-1 MAb can be Nivolumab. Nivolumab (also known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor Ab that selectively blocks interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449). In another embodiment, the anti-PD-1 mAb is pembrolizumab, and antigen-binding variants thereof. Pembrolizumab (also known as Lambrolizumab and MK-3475) are humanized monoclonal IgG4 antibodies against the human cell surface receptor PD1 (programmed death protein-1 or programmed cell death protein-1). Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587. In other embodiments, the anti-PD-1 MAb is MEDI0608 (formerly AMP-514), described, for example, in U.S. Patent No. 8,609,089. Other examples of humanized monoclonal antibodies include Pilizumab (CT-011), BGB-A317, etc., and antigen-binding variants thereof.

[0035] Another example of a suitable antibody is an anti-VEGF antibody, which is an antibody or antibody fragment (e.g., Fab or scFV fragment) that specifically binds to a VEGF receptor. Anti-VEGF antibodies act, for example, by interfering with the binding of VEGF to cell receptors, by interfering with the activation of vascular endothelial cells after the binding of VEGF to cell receptors, and / or by killing cells activated by VEGF. Anti-VEGF antibodies generally do not bind to other VEGF homologs (e.g., VEGF-B or VEGF-C) or other growth factors (e.g., PIGF, PDGF, or bFGF). Suitable anti-VEGF antibodies can include monoclonal and / or bispecific anti-VEGF antibodies, such as A4.6.1, bevacizumab, ranibizumab, G6, B20, 2C3, and other antibodies, such as those described in U.S. Patent Nos. 6,582,959, 6,703,020, 7,060,269, 7,169,901, 7,691,977, and 10,590,193; U.S. Patent Publication No. 2009 / 0169556; WO 94 / 10202; WO 98 / 45332; WO 96 / 30046; WO 2019 / 154776; WO 2010 / 040508; WO2011 / 117329; WO 2012 / 131078; WO 2015 / 083978; WO 2017 / 197199; and WO 2014 / 009465, which are all incorporated herein by reference. For example, the anti-VEGF antibody can be ranibizumab, bevacizumab, and their antigen-binding variants. Ranibizumab (molecular weight 48 kD) is a humanized monoclonal Fab fragment against VEGF-A having the light and heavy chain variable domain sequences of Y0317 as described in SEQ ID NOs. 115 and 116 of U.S. Patent No. 7,060,269. Ranibizumab inhibits endothelial cell proliferation and neovascularization and can be used to treat neovascular (wet) age-related macular degeneration (AMD), treat visual impairment caused by diabetic macular edema (DME), treat visual impairment caused by macular edema secondary to retinal vein occlusion (branch RVO or central RVO), or treat visual impairment caused by choroidal neovascularization (CNV) secondary to pathologic myopia. Bevacizumab (molecular weight 149 kD) is also a full-length humanized murine monoclonal antibody that can recognize all subtypes of VEGF and is the parental antibody of ranibizumab. In another embodiment, the anti-VEGF antibody can also be a bispecific antibody containing a first antigen-binding site that binds to human vascular endothelial growth factor (e.g., VEGF-A) and a second antigen-binding site that binds to human angiopoietin-2 (ANG-2).An example of such an anti-VEGF antibody is faricimab (molecular weight 150 kD) described in WO2019 / 154776 and WO2014 / 009465, which consists of an anti-Ang-2 antigen binding fragment (Fab), an anti-VEGF-A Fab and a modified fragment crystallizable region (Fc region).

[0036] Another suitable antibody is an anti-HER2 antibody. Such antibodies may be full-length anti-HER2 antibodies; anti-HER2 antibody fragments having the same biological activity; amino acid sequence variants and / or glycosylation variants comprising such antibodies or antibody fragments. Examples of humanized anti-HER2 antibodies include trastuzumab, pertuzumab, and margetuximab, as well as antigen-binding variants thereof. Other anti-HER2 antibodies with various properties have been described in Tagliabue et al., Int. J. Cancer, 47:933-937 (1991); McKenzie et al., Oncogene, 4:543-548 (1989); Cancer Res., 51:5361-5369 (1991); Bacus et al., Molecular Carcinogenesis, 3:350-362 (1990); Stancovski et al., PNAS (USA), 88:8691-8695 (1991); Bacus et al., Cancer Research, 52:2580-2589 (1992); Xu et al., Int. J. Cancer, 53:401-408 (1993); WO 94 / 00136; Kasprzyk et al., Cancer Research, 52:2771-2776 (1992); Hancock et al., Cancer Res., 51:4575-4580 (1991); Shawver et al., Cancer Res., 54:1367-1373 (1994); Arteaga et al., Cancer Res., 54:3758-3765 (1994); Harwerth et al., J. Biol. Chem., 267:15160-15167 (1992); US Patent No. 5,783,186; and Klapper et al., Oncogene, 14:2099-2109 (1997).

[0037] Typically, antibodies are present in preparations as naked antibodies. However, if necessary, antibodies can also be conjugated with other agents (e.g., cytotoxic agents). For example, when used to treat cancer, the immunoconjugates and / or antigens bound by the antibodies can be internalized by cells, thereby causing the therapeutic effect of the immunoconjugates to increase in killing cancer cells bound thereto. In one embodiment, cytotoxic agents target or interfere with nucleic acids in cancer cells. Examples of such cytotoxic agents include maytansinoid, calicheamicin, ribonucleases, and DNA endonucleases. Suitable immunoconjugates can include trastuzumab-maytansinoid immunoconjugates (T-DM1), such as T-MCC-DM1, whose chemical name is N-DM1. 2 '-Deacetyl-N 2 '-(3-Mercapto-1-oxopropyl)-maytansine-4-maleimidomethyl-cyclohexyl-1-carboxy-trastuzumab.

[0038] In another embodiment, for example, the antibody can be an anti-CTLA-4 (cytotoxic T lymphocyte-associated protein-4) antibody, for example, used as an immune checkpoint inhibitor for the treatment of cancer. CLTA-4 is a protein receptor that downregulates the immune system. As used herein, the term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants, isoforms and species homologs of hCTLA-4, and analogs having at least one common epitope with hCTLA-4. Specifically, CLTA-4 is an inhibitor of immunoglobulin cell surface receptors and T cell activation, and mainly expresses activated naive T cells and FoxP3+ regulatory T cells (Treg). T cell activation depends not only on the binding of T cell receptors (TCR) to antigens presented by adenomatous polyposis coli (APC), but also on the presence of a co-stimulatory second signal, usually through the binding of CD28 expressed on T cells to CD80 / 86 found on APC. The absence of this secondary signal may cause T cells to recognize presented peptides as "self-antigens" or develop tolerance to antigens. CTLA-4 is a competitive homolog of CD28. Compared with CD28, CTLA-4 has a higher affinity for CD80 (B7-1) and a lower affinity for CD 68 (B7-2), resulting in inhibition of T cell stimulation. TCR signaling immediately upregulates cell surface CTLA-4 expression, reaching peak expression 2 to 3 days after activation, providing a negative feedback loop after T cell activation. CTLA-4 in intracellular vesicles is also rapidly transported to the immune synapse after T cell activation. At the immune synapse, CTLA-4 is stabilized by CD80 / CD86 binding, allowing it to collect and inhibit CD28 binding. Therefore, the inclusion of anti-CTLA-4 antibodies can destroy the inhibitory mechanism of CTLA-4. Antibodies that specifically bind to CLTA-4 have been described in, for example, U.S. Pat. No. 6,984,720 and U.S. Pat. No. 10,196,445.

[0039] In certain embodiments, the anti-CTLA-4 antibody may be Ipilimumab. Ipilimumab (also known as Designated as MDX101) is a fully humanized IgG1κ immunoglobulin directed against CTLA-4. Ipilimumab has a molecular weight of approximately 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. Ipilimumab is a negative regulator of T cell activity. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands CD80 and CD86. Blockade of CTLA-4 by ipilimumab has been shown to enhance T cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T effector cells. Inhibition of CTLA-4 signaling may also reduce T regulatory cell function, which may contribute to the general increase in T cell reactivity, including anti-tumor immune responses.

[0040] Another suitable antibody is an anti-cKIT antibody. Such antibodies may be full-length anti-cKIT antibodies; anti-cKIT antibody fragments having the same biological activity; and amino acid sequence variants and / or glycosylation variants of such antibodies or antibody fragments. cKIT is a single transmembrane receptor tyrosine kinase inhibitor that binds to the ligand stem cell factor (SCF). As described by Kindblom et al., Am J. Path. 1998 152 (5): 1259, SCF induces homodimerization of cKIT, activates its tyrosine kinase activity and signals through the PI3-AKT and MAPK pathways. Anti-cKIT antibodies with various properties are described in Gadd et al., Leuk. Res. 1985 (9): 1329, Broudy et al., Blood 1992 79 (2): 338, U.S. Pat. No. 8,552,157, and U.S. Pat. No. 9,540,443.

[0041] Another suitable antibody is anti-4-1BB antibody (anti-CD137).CD137 (4-1BB) is a member of the tumor necrosis receptor (TNF-R) gene family including proteins involved in regulating cell proliferation, differentiation and programmed cell death.Suitable anti-4-1BB antibodies include urelumab (BMS-663513), which is a fully human IgG4 monoclonal antibody.Other suitable anti-4-1BB antibodies are described in U.S. Patent No. 7,288,638, U.S. Patent No. 7,659,384, U.S. Patent No. 8,137,667, U.S. Patent No. 10,875,921, U.S. Patent No. 11,242,395.

[0042] Typically, antibodies are present in formulations as naked antibodies. However, if desired, the therapeutic agent may include an antibody drug conjugate (ADC). ADCs are a rapidly growing class of targeted therapeutics that represent a promising new approach to improving the selectivity and cytotoxic activity of cancer drugs (e.g., cytotoxic agents). ADCs have three components: (1) a monoclonal antibody coupled to (2) a linker and (3) a cytotoxin. The cytotoxin is attached to a lysine or cysteine ​​side chain on the antibody via a linker that selectively reacts with primary amines on lysine or with sulfhydryl groups on cysteine.

[0043] The maximum number of joints / drugs that can be coupled depends on the number of reactive amino groups or sulfhydryl groups present on the antibody. Typical antibodies contain up to 90 lysines as potential coupling sites; however, for most ADCs, due to the aggregation of ADCs with higher numbers of cytotoxins, the typical number of cytotoxins per antibody is usually between 2 and 4. Therefore, the ADCs connected by conventional lysines are heterogeneous mixtures, which contain 0 to 10 cytotoxins per antibody coupled to different amino groups on the antibody. Antibody cysteine ​​can also be used for coupling with cytotoxins by joints containing maleimide or other thiol-specific functional groups. Typical antibodies contain 4 or sometimes 5 interchain disulfide bonds (2 between heavy chains, and 2 between heavy chains and light chains) that covalently bond heavy chains and light chains together and contribute to the stability of antibodies in vivo. These interchain disulfides can be selectively reduced with dithiothreitol, tris (2-carboxyethyl) phosphine or other mild reducing agents to provide 8 reactive sulfhydryl groups for coupling. Because there are fewer potential conjugation sites, cysteine-linked ADCs are less heterogeneous than lysine-linked ADCs; however, they also tend to be less stable due to partial loss of interchain disulfide bonds during conjugation, as current cysteine ​​linkers are only bonded to one sulfur atom. For cysteine-linked ADCs, the typical number of cytotoxins per antibody is also 2 to 4. For example, ADCETRIS is a heterogeneous mixture containing 0 to 8 monomethylauristatin E residues per antibody conjugated via cysteine.

[0044] Key factors for the success of ADCs include: monoclonal antibodies are cancer antigen specific, non-immunogenic, low in toxicity, and internalized by cancer cells; cytotoxins are highly potent and amenable to linker attachment; although linkers may be specific for cysteine ​​(S) or lysine (N) binding, they are stable in circulation, may be protease cleavable and / or pH sensitive, and suitable for attachment to cytotoxins. When used to treat cancer, for example, the ADC and / or antigen to which the antibody binds may be internalized by the cell, resulting in increased therapeutic efficacy of the ADC in killing the cancer cells to which it binds.

[0045] ADCs may include at least one monoclonal antibody described above and at least one cytotoxic agent (e.g., a chemotherapeutic agent as described below). For example, ADCs may include an anti-CLTA-4 antibody (e.g., ipilimumab) linked to one or more chemotherapeutic agents. For another example, ADCs may include an anti-PD1 antibody (e.g., nivolumab, pembrolizumab, or pilumab) linked to one or more chemotherapeutic agents. For another example, ADCs may include an anti-VEGF antibody (e.g., faricitumab) linked to one or more chemotherapeutic agents. For another example, ADCs may include an anti-HER2 antibody (e.g., trastuzumab, pertuzumab, and magituximab) linked to one or more chemotherapeutic agents. For another example, ADCs may include an anti-cKIT antibody linked to one or more chemotherapeutic agents. Suitable ADCs including anti-cKIT antibodies are described in PCT Publication No. WO 2014 / 150937.

[0046] The number of molecules of a drug (e.g., a chemotherapeutic agent) coupled to each antibody is referred to as the drug-antibody ratio (DAR). DAR can affect the potency and overall toxicity of an ADC. For example, if the DAR is too low, the ACD may not provide therapeutically effective results, and if the DAR is too high, the patient may experience undesirable side effects. Given reaction and processing conditions, the DAR of an ADS is generally in any range of 0 to 15, such as about 0 to 8. Therefore, the disclosed ADC can have a DAR of 0 to 15, such as 1 to 14, such as 2 to 13, such as 3 to 12, such as 4 to 11, such as 5 to 10, such as 6 to 9. In certain embodiments, the ADC has a DAR of 2 to 4.

[0047] The DAR of a manufacturing batch of ADC can be determined empirically using spectrophotometric measurements, and ADC therapeutic compositions typically contain a mixture of ADC species with different drug loadings. Therefore, the DAR of an ADC batch represents the average DAR of the ADC species within the batch. The different DARs of each batch can lead to potency variability. In order to reduce potency variability, the ADC contained in the batch used in the pharmaceutical preparation of the present application may include an average DAR of about 2 to about 8, such as about 2 to about 6, such as about 2 to 4. In a certain embodiment, the average DAR of the ADC is about 3 to about 5, such as about 4.

[0048] ADCs suitable for use in the pharmaceutical formulations of the present disclosure that are approved by the FDA also include gemtuzumab ozogamicin, Mylotarg TM ), brentuximab vedotin, Adetris TM ), trastuzumab ematansine, Kadcyla TM), inotuzumab ozogamicin (Besponsa TM ), moxetumomab pasudotox, Lumoxiti TM ), polatuzumab vedotin-piiq (Polivy TM ), enfortumab vedontin, Padcev TM ), trastuzumab deruxtecan, Enhertu TM ), sacituzumab govitecan (Trodelvy TM ), sacituzumab govitecan, Blenrep TM ), locastuximab tesirine-lpyl, Zylonta TM ), tisotumab vedotin-tftv (Tivdak TM ), and combinations thereof. Other suitable ADCs include mirvetuximab soravtansine (IMGN 853), transtuzumab duocarmazine (SYD985), depatuxizumab mafodotin (AGX-414), disitimab vedotin (RC48-ADC) and combinations thereof. Other suitable ADCs include mirvetuximab soravtansine (IMGN853), transtuzumab duocarmazine (SYD985), depatuxizumab mafodotin (ABT-414), disitimab vedotin (RC48-ADC) and combinations thereof. In other embodiments, ADCs may include antibodies linked to other types of molecules, such as oligonucleotides, radionuclides, and protein toxins.

[0049] The antibodies of the present disclosure may also include radiolabeled antibodies. Such antibodies include a radioactive substance coupled to the antibody that is configured to provide radioactivity directly to cancer cells. Suitable radiolabeled antibodies include ibritumomab tiuxetan, Zevalin TM ). Radiolabeled antibodies include any of the antibodies disclosed herein coupled to a radioactive substance (e.g., yttrium-90). Other radiolabeled antibodies are described in International Patent Application No. WO2009 / 0538203 and U.S. Patent Application No. 7,402,385.

[0050] The antibodies disclosed herein may also include multispecific antibodies, such as bispecific antibodies (BsAbs). A multispecific antibody refers to any antibody that can bind to two or more different antigens at the same time, while a BsAb refers to an antibody that can bind to two different antigens at the same time. An example BsAb is a bispecific T cell engager (BiTE), in which one arm targets CD3 on T cells and the other arm recognizes a target protein on tumor cells, thereby activating T cells to kill tumor cells. In addition to their interaction with T cells, BsABs are also designed to engage other effector cells, such as natural killer (NK) cells and macrophages for cancer treatment. Suitable BsAbs include blinatumomab (BLINCYTO 1901), which targets both CD19 and CD3. TM ) and catumaxomab (Removab) targeting human EpCAM and human CD3 receptors TM Other suitable BsAbs include AMG 330 (anti-CD 3 / CD33), AMG 427 (anti-CD3 / FLT3), AMG 673 (anti-CD 3 / CD33), AMG 701 (anti-CD3 / BCMA), AMG 160 (anti-CD3 / prostate-specific membrane antigen (PSMA)), AMG 596 (anti-CD3 / epidermal growth factor receptor (EGFR)) and AMG 757 (anti-CD3 / DLL-3), all of which are developed by Amgen.

[0051] Other suitable BsABs or multispecific antibodies may include those currently approved by the FDA and / or being tested in clinical trials, including blinatumomab / Blincyto / MT103 / MEDI-538 / AMG103 (clinical trial identification number NCT01466179 NCT02013167), AFM11 (clinical trial identification number NCT02848911), AMG562 (clinical trial identification number NCT03571828), REGN1979 (clinical trial identification number NCT03888105), Glofitamab / RO7082859 (clinical trial identification number NCT03075696), Plamotamab / XmAb13676 (clinical trial identification number NCT02924402), Moxontumomab (Mosunetuzumab) / RG7828 / RO703081 (clinical trial identification number NCT04313608), GEN3013 (clinical trial identification number NCT03625037), AMG673 (clinical trial identification number NCT03224819), AMV-564 (clinical trial identification number NCT03144245), ISB1342 (clinical trial identification number NCT03309111), JNJ-63709178 (clinical trial identification number NCT02715011), SAR 440234 (clinical trial identification number NCT03594955), vibecotamab / Xmab 14045 (clinical trial identification number NCT02730312), AMG420 / BI836909 (clinical trial identification number NCT03836053), CC-93269 / EM801 (clinical trial identification number NCT03486067), teclistamab / JNJ-64007957 (clinical trial identification number NCT04557098), PF-06863135 (clinical trial identification number NCT04649359), REGN5458 (clinical trial identification number NCT03761108), catumaxomab / removab (clinical trial identification number NCT03070392), RG6194 / BTRC4017 A (clinical trial identification number NCT03448042), M802 (clinical trial identification number NCT04501770), GBR1302 (clinical trial identification number NCT03983395), Cibisatamab / RG7802 / RO6958688 (clinical trial identification number NCT03866239), AMG211 (clinical trial identification number NCT02291614), AMG160 (clinical trial identification number NCT03792841), MOR209 / ES414 (clinical trial identification number NCT02262910), Pasotuxizumab / BAY2010112 (clinical trial identification number NCT01723475), REGN5678 (clinical trial identification number NCT03972657), FS120 (clinical trial identification number NCT04648202), PRS-343 (clinical trial identification number NCT03330561), AFM13 (clinical trial identification numbers NCT03192202, NCT04101331), AFM24 (clinical trial identification number NCT04259450), GTB-3550, OXS-35504 (clinical trial identification number NCT03214666) , MEDI5752 (clinical trial identification number NCT04522323), AK104 (clinical trial identification number NCT04172454), XmAb20717 (clinical trial identification number NCT03517488), MGD019 (clinical trial identification number NCT03761017), MGD013 (clinical trial identification number NCT03219268), RO7121661, RG7769 (clinical trial identification number Identification number NCT03708328), KN046 (clinical trial identification number NCT03872791, NCT04474119, NCT04469725, NCT03733951), FS118 (clinical trial identification number NCT03440437), LY3415244 (clinical trial identification number NCT03752177), IBI318 / LY3434172 (clinical trial identification number NCT 03875157), IBI315 IBI318 / LY3434172 (clinical trial identification number NCT 04162327), AK112 (clinical trial identification number NCT04047290), IBI319 (clinical trial identification number NCT04708210), FS222 (clinical trial identification number NCT04740424), MCLA-145 (clinical trial identification number NCT 03922204), ATOR 1015 (clinical trial identification number NCT03782467), XmAb23104 (clinical trial identification number NCT03752398), TG-1801 / NI-1701 (clinical trial identification number NCT03804996), IMM0306 (clinical trial identification number CTR20192612), IBI322 (clinical trial identification number NCT04338659, NCT04328831), HX009 (clinical trial identification number NCT04097769), JNJ-61186372 / Amivantamab (clinical trial identification number NCT 02609776), MCLA-158 (clinical trial identification number NCT03526835), MCLA-128 / Zenocutuzumab (clinical trial identification number NCT03321981), KN026 (clinical trial identification number NCT04521179), MBS301 (clinical trial identification number NCT 03842085), ZW25 (clinical trial identification number NCT02892123), ZW49 (clinical trial identification number NCT03821233), MM-141 (clinical trial identification number NCT02399137), BI836880 (clinical trial identification numbers NCT03972150, NCT03697304), RO5520985 / Vanucizumab (clinical trial identification number NCT0214129 5), ABT-165 / Dilpacimab (clinical trial identification number NCT01946074), OMP-305B83 / Navicixizumab (clinical trial identification number NCT03030287), RG7386 / RO6874813 (clinical trial identification number NCT02558140), OXS-1550 / DT2219ARL (clinical trial identification number NCT02370160) and their combinations.

[0052] As described above, antibodies may include antibody fragments (Fab). Such FDA-approved Fabs include ranibizumab (Ranibizumab, Lucentis TM ), Abciximab (ReoPro TM ), Certolizumab pegol, Cimzia TM ), Idarucizumab (Praxbind TM ), Digoxin Immune Fab (Digoxin Immune Fab, DigiFab TM ), multivalent Crotalidae immune Fab (CroFab TM ), polyvalent arotalidae immune Fab (Anavip TM ), Anascorpion immune F(ab')2 (Anascorp TM), Brolucizumab (Beovu TM ), Caplacizumab, Cablivi TM ) or a combination thereof. In addition, Fabs that can be used in the device also include copper Cu 64-DOTA-B-Fab (clinical trial identification number NCT02708511), CSR 02-Fab-TF (clinical trial identification number NCT04601428), ranibizumab (Ranibizumab, clinical trial identification number NCT 00540930), Naptumomab estafenatox) (clinical trial identification number NCT00420888), IMCgp100 (clinical trial identification number NCT01209676), L19-IL2 (clinical trial identification number NCT02086721), rM28 (clinical trial identification number NCT00204594), D2C7-IT (clinical trial identification number NCT02303678), NM21-1480 (clinical trial identification number NCT04442126), Vicinium (clinical trial identification number NCT02449239), [124I]PSCA-miniantibody (clinical trial identification number NCT02092948), 6B11-OCIK (clinical trial identification number NCT03542669), T84.66 (clinical trial identification number NCT00647153), BCMA VHH CAR-T cells (clinical trial identification number NCT 03664661), CD19 / 20 bispecific VHH-derived CAR-T cells (clinical trial identification number NCT03881761), ALX-0651 (clinical trial identification number NCT01374503), αPD1-MSLN-CAR T cells (clinical trial identification numbers NCT 04489862, NCT 04503980), [131I]-SGMIB anti-HER2 VHH1 (clinical trial identification number NCT02683083), 68-Ga NOTA-anti-MMR-VHH2 (clinical trial identification number NCT04168528), 68-GaNOTA-anti-HER 2VHH1VHH (clinical trial identification numbers NCT03924466, NCT03331601), 99mTc-MIRC208 (clinical trial identification number NCT 04591652), TAS226 (clinical trial identification number NCT01529307), and their combinations.

[0053] In an embodiment, the antibody may include an antibody-cytokine fusion protein fusion protein, referred to as an immunocytokine. Cytokines constitute a relatively small class of proteins that regulate immune responses that are widely and loosely defined. Systemic administration of proinflammatory cytokines is often associated with severe off-target toxicity, particularly flu-like symptoms, which may limit the dose and prevent the increase in the dose required for the development of a therapeutically effective regimen. Similar to ADC, cytokines using antibodies or antibody fragments as carriers have been used for targeted delivery of immunomodulatory cytokines (e.g., interleukin (IL) -2, IL-12, and tumor necrosis factor (TNF), including TNFα and TNFb) to utilize the local tumor microenvironment (TME) and activate anticancer immune responses. Suitable immunocytokines that can be used according to the present disclosure include, but are not limited to, L19IL2 (clinical trial identification number NCT01058538), L19TNFα (clinical trial identification number NCT01253837), F16IL2 (clinical trial identification number NCT01134250), hu14.18-IL2 (clinical trial identification number NCT00003750), huKS-IL2 (EMD273066) (clinical trial identification number NCT00132522), DI-Leu16-IL2 (anti-CD20-IL2) (clinical trial identification number NCT01374288), NHS-IL12 (clinical trial identification number NCT04303117), NHS-IL2-LT (EMD521873) (clinical trial identification number NCT00879866), anti-CEA-IL2v (amleukin-2-cergutuzumab, cergutuzumab amunaleukin) (clinical trial identifier NCT02350673) and combinations thereof.

[0054] The antibodies disclosed herein also include antibody-small interfering RNA (siRNA) conjugates (ARC). Since antibodies show high specificity to antigens overexpressed in certain cell types or tissues, antibodies can be used for targeted delivery of siRNA molecules. siRNA molecules can be connected to antibodies with covalent bonds to lysine or cysteine ​​residues. Therefore, the antibodies used herein may include the disclosed antibodies connected to one or more siRNA molecules for the treatment of cancer. This ARC can be used to treat a variety of cancers. There are several disadvantages in using ARC to treat cancer, namely, ARC may not easily enter cells due to the negative charge of the attached siRNA, which makes it difficult to overcome the thermodynamic barrier presented by the cell membrane. Therefore, ARC can be incorporated into the device disclosed herein and released in the tumor cell itself, thereby eliminating the thermodynamic barrier at the cell membrane.

[0055] Regardless of the type of antibody employed, it is generally stable at sufficiently high temperatures so that during manufacture or use of the device, the antibody can be incorporated into the polymer matrix without significant degradation (e.g., melting) at or near the melting temperature of the polymer matrix. For example, the antibody can be stable at a temperature of about 20°C to about 100°C, in some embodiments about 25°C to about 80°C, in some embodiments about 30°C to about 70°C, in some embodiments about 35°C to about 65°C, and in some embodiments about 40°C to about 60°C. The antibody can be inherently stable at such temperatures, or it can also be encapsulated or otherwise protected by a carrier component that is stable at such temperatures, such as a carrier component comprising a peptide, protein, carbohydrate (e.g., saccharide), polymer, lipid, etc.

[0056] In certain embodiments, the pharmaceutical preparation may contain only an antibody (e.g., an antibody) as a therapeutic agent. Of course, in other embodiments, the preparation may contain a combination of an antibody and one or more additional types of therapeutic agents. Such additional therapeutic agents may be macromolecular compounds with a relatively large molecular weight, such as a molecular weight of 1 kilodalton (kDa) or greater, in some embodiments about 2kDa to about 1000kDa, in some embodiments about 20kDa to about 950kDa, in some embodiments about 50kDa to about 750kDa, and in some embodiments about 100kDa to about 500kDa, or any range therebetween. Macromolecular compounds may include, for example, proteins, peptides, enzymes, antibodies, interferons, interleukins, blood factors, vaccines, nucleotides, lipids, or analogs, derivatives, or combinations thereof. Alternatively, small molecule therapeutic agents may be used, such as small molecule therapeutic agents having a molecular weight of less than about 1,000Da, in some embodiments about 900Da or less, in some embodiments about 10 to about 800Da, and in some embodiments about 20 to about 700Da, or any range therebetween.

[0057] Specific examples of suitable additional therapeutic agents may include, for example, proteins, peptides, enzymes, antibodies, interferons, interleukins, blood factors, vaccines, nucleotides, lipids, small molecule drug compounds, etc., and analogs, derivatives, and combinations thereof.For example, therapeutic agents may include nonsteroidal anti-inflammatory drugs (e.g., salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam); antiallergic drugs (e.g., sodium cromolyn, antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine); antiproliferative agents (e.g., 1,3-cis retinoic acid); decongestants (e.g., phenylephrine, naphazoline, tetrahydrazoline); miotic and anticholinesterase agents (e.g., pilocarpine); pilocarpine, salicylates, carbachol, acetylcholine chloride, physostigmine, eserine, diisopropyl fluorophosphate, diethiophosphocholine iodine, demecarium bromide); antineoplastic agents (e.g., carmustine, cisplatin, fluorouracil); immunological drugs (e.g., vaccines and immunostimulants); hormone preparations (e.g., estrogens, estradiol, progestins, progesterone, insulin, calcitonin, parathyroid hormone, peptides and vasopressin hypothalamic releasing factor); immunosuppressants, growth hormone antagonists, growth factors (e.g., epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β, growth hormone, fibronectin); angiogenesis inhibitors (e.g., angiostatin, anecortave acetate, interferons (e.g., interferon alpha-2b, PEG interferon alpha-2a, interferon alpha-2b + ribavirin, pegylated interferon-2a, interferon beta-1a, interferon beta); interleukins (e.g., interleukin-2); vaccines (e.g., whole virus particles, recombinant proteins, subunit proteins, gp41, gp120, gp140, DNA vaccines, plasmids, bacterial vaccines, polysaccharides, extracellular capsular polysaccharides); dopamine agonists; radiotherapeutic agents ; peptides; proteins; enzymes; extracellular matrix components; ACE inhibitors; free radical scavengers; chelators; antioxidants; anti-polymerase agents; photodynamic therapy agents; gene therapy agents; corticosteroids (e.g., dexamethasone), tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ponatinib, ruxolitinib, sorafenib, sunitinib, vatalanib, vemurafenib, etc.), etc., and combinations of any of the above drugs.

[0058] B. excipient

[0059] In some embodiments, pharmaceutical preparations can contain only therapeutic agents (e.g., antibodies). Since therapeutic agents are generally water-soluble, the relative amount of such agents can be selectively controlled to help achieve the desired release rate. That is, when only therapeutic agents are present, the weight ratio of therapeutic agents to polymer matrix is ​​generally controlled within the range of about 0.7 to about 1, about 0.75 to about 1 in some embodiments, about 0.75 to about 0.9 in some embodiments, and about 0.8 to about 0.85 in some embodiments, and therapeutic agents can constitute about 40wt.% to about 50wt.% of device equally, about 41wt.% to about 48wt.% in some embodiments, and about 42wt.% to about 47wt.% in some embodiments.

[0060] Of course, as mentioned above, pharmaceutical preparations can also optionally contain one or more excipients, such as buffer, saccharide (for example, sugar, sugar alcohol etc.), surfactant, antimicrobial agent, preservative, cell permeability enhancer etc., to enhance performance and processability. Because these excipients are normally water-soluble, the relative amounts of these excipients can also be selectively controlled to help realize required release rate. For example, when there is excipient, the weight ratio of therapeutic agent to polymer matrix can be about 0.3 to about 1, about 0.75 to about 1 in some embodiments, about 0.35 to about 0.5 in some embodiments, and about 0.38 to about 0.45 in some embodiments. Likewise, optional excipients may constitute from about 10 wt.% to about 80 wt.%, in some embodiments from about 20 wt.% to about 70 wt.%, and in some embodiments from about 40 wt.% to about 60 wt.% of the pharmaceutical formulation, and the therapeutic agent (e.g., an antibody) may likewise constitute from 20 wt.% to about 90 wt.%, in some embodiments from about 30 wt.% to about 80 wt.%, and in some embodiments from about 40 wt.% to about 60 wt.% of the pharmaceutical formulation.

[0061] The pH value of the pharmaceutical preparation can be, for example, ideally in the range of about 5.5 to about 7.5, and in some embodiments in the range of about 5.7 to about 6.3. In order to help reach the desired level, one or more buffers can be used. Exemplary buffers can include, for example, histidine buffers, such as L-histidine, L-histidine hydrochloride, L-histidine hydrochloride monohydrate, histidine succinate, histidine acetate, histidine citrate, histidine chloride or histidine sulfate, etc., and combinations thereof. Other suitable buffers can include, for example, salts of metals (e.g., sodium) and acids (e.g., carboxylic acids (e.g., acetic acid, succinic acid, citric acid, etc.), phosphoric acid, etc.). Such salts can include, for example, sodium succinate, sodium acetate, sodium acetate / acetic acid, sodium phosphate, etc. When used, optional buffers can constitute about 0.01wt.% to about 20wt.%, in some embodiments about 0.1wt.% to about 10wt.%, and in some embodiments about 0.5wt.% to about 5wt.%. of the pharmaceutical preparation.

[0062] If necessary, one or more sugars can also be used in the formulation to help act as degradation stabilizers for antibodies. Particularly suitable sugars include, for example, monosaccharides (e.g., glucose, fructose, galactose, ribose, deoxyribose, etc.); disaccharides (e.g., sucrose, lactose, maltose, trehalose, etc.); sugar alcohols (e.g., xylitol, sorbitol, mannitol, maltitol, erythritol, galactitol, inositol, lactitol, etc.); and the like, and combinations thereof. Trehalose (e.g., α, α-trehalose or α, α-trehalose dihydrate) is particularly suitable for use in formulations. When used, sugars may constitute about 10wt.% to about 70wt.%, and in some embodiments about 20wt.% to about 65wt.%, and in some embodiments about 30wt.% to about 60wt.% of the pharmaceutical formulation.

[0063] Surfactants can also be used as optional stabilizers for formulations. Nonionic surfactants that generally have a hydrophobic base (e.g., a long-chain alkyl or alkylated aryl) and a hydrophilic chain (e.g., a chain containing an ethoxy and / or propoxy moiety) are particularly suitable. Some suitable nonionic surfactants that can be used include, but are not limited to, ethoxylated alkylphenols, ethoxylated and propoxylated fatty alcohols, polyethylene glycol ethers of methyl glucose, polyethylene glycol ethers of sorbitol, ethylene oxide-propylene oxide block copolymers, fats (C8-C 18) Ethoxylated esters of acids, condensation products of ethylene oxide with long-chain amines or amides, condensation products of ethylene oxide with alcohols, fatty acid esters, monoglycerides or diglycerides of long-chain alcohols, and mixtures thereof. Particularly suitable nonionic surfactants may include ethylene oxide condensates of fatty alcohols, polyoxyethylene ethers of fatty acids, polyoxyethylene sorbitan fatty acid esters, and sorbitan fatty acid esters, etc. The fat component used to form such emulsifiers may be saturated or unsaturated, substituted or unsubstituted, and may contain 6 to 22 carbon atoms, in some embodiments 8 to 18 carbon atoms, and in some embodiments 10 to 14 carbon atoms. Sorbitan fatty acid esters (e.g., monoesters, diesters, triesters, etc.) that have been modified with polyoxyethylene are a group of particularly useful nonionic surfactants. These materials are typically prepared by adding ethylene oxide to 1,4-sorbitan esters. The addition of polyoxyethylene converts the lipophilic sorbitan ester surfactants into hydrophilic surfactants that are generally soluble or dispersible in water. Examples of such materials may be named (For example 20 or polyethylene (20) sorbitan monolaurate) is commercially available. When used, the surfactant may constitute from about 0.001 wt.% to about 5 wt.%, and in some embodiments from about 0.01 wt.% to about 2 wt.%, and in some embodiments from about 0.05 wt.% to about 1 wt.% of the solid content of the pharmaceutical formulation.

[0064] If desired, the pharmaceutical preparation may be a commercially available antibody preparation for treating certain conditions. For example, a suitable pharmaceutical preparation may be HERCEPTIN TM , which contains a combination of anti-HER2 monoclonal antibody (trastuzumab) and α,α-trehalose dihydrate, L-histidine, L-histidine hydrochloride and polyethylene (20) sorbitan monolaurate. Another suitable formulation may be AVASTIN TM , which contains an anti-VEGF monoclonal antibody (bevacizumab) and a combination of trehalose dihydrate, sodium phosphate and polyethylene (20) sorbitan monolaurate. Similarly, another suitable formulation may be XOLAIR TM , which contains an anti-IgE monoclonal antibody (omalizumab) and a combination of sucrose, histidine, histidine hydrochloride monohydrate and polyethylene (20) sorbitan monolaurate.

[0065] No matter use any optional excipient, generally all hope that pharmaceutical preparation is the form of dehydrated particulate material before being mixed into polymer matrix.In some embodiments, for example, liquid preparation can be dehydrated under reduced pressure using standard freeze drying equipment or equivalent device.Antibody and / or other excipient also can be frozen in liquid nitrogen before dehydration, then be placed under reduced pressure.Also can adopt spray drying to form this particulate material.In addition, can adopt various technology (for example electrostatic method) to atomize droplet and allow to use lower temperature.

[0066] III. Implantable Devices

[0067] Implantable devices can be formed by various known techniques, such as by hot melt extrusion, injection molding, solvent casting, dip coating, spraying, micro extrusion, coagulation, etc. In one embodiment, hot melt extrusion technology can be used. Hot melt extrusion is generally a solvent-free process, wherein the components of the device (such as hydrophobic polymers, antibodies, optional excipients, etc.) can be melt blended and optionally shaped in a continuous manufacturing process, thereby achieving consistent output quality with a high throughput rate. This technology is particularly well suited for certain types of hydrophobic polymers (such as ethylene-vinyl acetate) that can generally show high long-chain branching and have a wide molecular weight distribution. The combination of this character can cause shear thinning of the copolymer during extrusion, which helps to promote hot melt extrusion. In addition, the polar comonomer unit can act as an "internal" plasticizer by suppressing the crystallization of the olefin segment. This can result in a lower melting point of the polymer, which further enhances its ability to be processed with the antibody.

[0068] In the hot melt extrusion process, melt blending is generally carried out at a temperature similar to or even lower than the temperature at which the antibody melts. Melt blending can also be carried out at a temperature similar to or slightly higher than the melting temperature of the hydrophobic polymer. The ratio of the melt blending temperature to the antibody degradation temperature can be, for example, about 2 or lower, about 1.8 or lower in some embodiments, about 0.1 to about 1.6 in some embodiments, about 0.2 to about 1.5 in some embodiments, and about 0.4 to about 1.2 in some embodiments. The melt blending temperature can be, for example, about 30°C to about 100°C, about 40°C to about 80°C in some embodiments, and about 50°C to about 70°C in some embodiments. Any technology in various melt blending techniques can generally be used. For example, the components can be supplied to an extruder separately or in combination, and the extruder includes at least one screw that can be rotatably mounted and housed in a barrel (e.g., a cylindrical barrel). The extruder can be a single screw or a twin screw extruder. For example, one embodiment of a single screw extruder may include a housing or barrel and a screw that can be driven to rotate at one end by a suitable drive device (typically including a motor and a gearbox). If desired, a twin screw extruder comprising two separate screws may be used. The configuration of the screw is not particularly critical, and it may include threads and channels of any number and / or orientation as known in the art. For example, the screw typically includes threads that form a substantially spiral channel extending radially around the center of the screw. A feed section and a melting section may be defined along the length of the screw. The feed section is the input portion of the barrel to which a hydrophobic polymer and / or antibody is added. The melting section is a phase change section where the copolymer changes from a solid to a liquid-like state. Although there is no precise delineation of these sections when manufacturing the extruder, it is entirely within the ordinary capabilities of those in the art to reliably identify the feed section and the melting section where a phase change from solid to liquid occurs. Although not necessarily required, the extruder may also have a mixing section adjacent to the output end of the barrel and located downstream of the melting section. If desired, one or more distributive and / or dispersive mixing elements may be used within the mixing and / or melting section of the extruder. Suitable distributive mixers for single screw extruders may include, for example, Saxon, Dulmage, cavity transfer mixers, and the like. Likewise, suitable dispersive mixers may include bubble rings, Leroy / Maddock, CRD mixers, and the like. As is well known in the art, mixing may be further improved by using pins in the barrel that cause folding and redirection of the polymer melt, such as those used in Buss kneading extruders, cavity transfer mixers, and vortex bite pin mixers.

[0069] If desired, the ratio of the length ("L") to the diameter ("D") of the screw can be selected to achieve an optimal balance between the throughput and blending of the components. The L / D value can be, for example, from about 10 to about 50, from about 15 to about 45 in some embodiments, and from about 20 to about 40 in some embodiments. The length of the screw can be, for example, from about 0.1 to about 5 meters, from about 0.4 to about 4 meters in some embodiments, and from about 0.5 to about 2 meters in some embodiments. Similarly, the diameter of the screw can be from about 5 to about 150 millimeters, from about 10 to about 120 millimeters in some embodiments, and from about 20 to about 80 millimeters in some embodiments. In addition to the length and diameter, other aspects of the extruder can also be selected to help achieve the desired degree of blending. For example, the speed of the screw can be selected to achieve the desired residence time, shear rate, melt processing temperature, etc. For example, the screw speed range can be from about 10 to about 800 revolutions per minute ("rpm"), from about 20 to about 500 rpm in some embodiments, and from about 30 to about 400 rpm in some embodiments. The apparent shear rate during melt blending may also range from about 100 sec -1 to about 10,000 seconds -1 , in some embodiments about 500 seconds -1 to about 5000 seconds -1 , and in some embodiments about 800 seconds -1 to about 1200 seconds -1 The apparent shear rate is equal to 4Q / πR 3 , where Q is the volume flow rate of the polymer melt (“m 3 / s”) and R is the radius (“m”) of the capillary (e.g., extruder die) through which the molten polymer flows.

[0070] Once melt blended together, the resulting polymer composition can be extruded through an orifice (e.g., a die) and formed into pellets, sheets, fibers, filaments, etc., which can then be formed into implantable devices using various known molding techniques, such as injection molding, compression molding, nano molding, overmolding, blow molding, three-dimensional printing, etc. Injection molding can occur, for example, in two main stages, namely the injection stage and the holding stage. In the injection stage, the mold cavity is filled with a molten polymer composition. The holding stage begins after the injection stage is completed, wherein the holding pressure is controlled to fill other materials into the cavity and compensate for the volume shrinkage that occurs during cooling. After the shot has been molded, it can be subsequently cooled. Once cooling is completed, the molding cycle is completed when the mold is opened and the parts are discharged, such as by means of a ejector pin in the mold. Any suitable injection molding equipment can generally be used in the present invention. In one embodiment, an injection molding device that can be used includes a first mold base and a second mold base, which together define a mold cavity having the shape of an implantable device. The molding device includes a resin flow path extending from the outer surface of the first mold half through a gate to the mold cavity. Various techniques can be used to supply the polymer composition to the resin flow path. For example, the composition can be supplied (for example, in the form of pellets) to a feed hopper attached to an extruder barrel comprising a rotating screw (not shown). As the screw rotates, the pellets move forward and are subjected to pressure and friction, which generates heat to melt the pellets. A cooling mechanism can also be provided to solidify the resin into the desired shape (for example, a disk, a rod, etc.) of an implantable device in the mold cavity. For example, the mold base may include one or more cooling lines, and a cooling medium flows through the line to impart the desired mold temperature to the surface of the mold base, thereby solidifying the molten material. The mold temperature (for example, the temperature of the mold surface) range may be from about 50°C to about 120°C, from about 60°C to about 110°C in some embodiments, and from about 70°C to about 90°C in some embodiments.

[0071] As described above, another suitable technique for forming an implantable device having a desired shape and size is three-dimensional printing. In this process, the polymer composition can be incorporated into a printer cartridge that is easily applicable to a printer system. The printer cartridge can, for example, include a spool or other similar device that carries the polymer composition. For example, when supplied in the form of a filament, the spool can have a generally cylindrical edge around which the filament is wound. The spool can also define a hole or a mandrel to allow it to be easily installed to the printer during use. The present invention can employ any of a variety of three-dimensional printer systems. A particularly suitable printer system is an extrusion-based system, which is generally referred to as a "fused deposition modeling" system. For example, the polymer composition can be supplied to a build chamber of a print head including a platen and a gantry. The platen can be moved along a vertical z-axis based on a signal provided by a computer-operated controller. The gantry is a rail system that can be configured to move the print head in a horizontal xy plane in the build chamber based on a signal provided by the controller. The print head is supported by the gantry and is configured to print a build structure on the platen in a layer-by-layer manner based on a signal provided by the controller. For example, the print head can be a dual-head extruder.

[0072] Compression molding (e.g., vacuum compression molding) may also be used. In such a method, the layer of the device may be formed by heating and compressing the polymer into a desired shape under vacuum. More specifically, the process may include forming the polymer composition into a precursor adapted to the chamber of a compression mold, heating the precursor, and compression molding the precursor into a desired layer while heating the precursor. The polymer composition may be formed into a precursor by a variety of techniques (e.g., by dry powder mixing, extrusion, etc.). The temperature range during compression may be from about 50°C to about 120°C, from about 60°C to about 110°C in some embodiments, and from about 70°C to about 90°C in some embodiments. A vacuum source may also apply negative pressure to the precursor during molding to help ensure that it maintains a precise shape. Examples of such compression molding techniques are described in, for example, U.S. Pat. No. 10,625,444 to Treffer et al., the entire contents of which are incorporated herein by reference.

[0073] The resulting implantable medical device can have a variety of different geometric shapes, such as cylindrical (rod), disc-shaped, annular, donut-shaped, spiral, elliptical, triangular, oval, etc. For example, in one embodiment, the implantable medical device can have a substantially circular cross-section so that the overall structure is a cylindrical (rod) or disc form. The implantable medical device also has a relatively small size, such as a thickness (e.g., diameter) of about 0.1 mm to about 10 mm, about 0.1 mm to about 5 mm in some embodiments, about 0.3 mm to about 2 mm in some embodiments, and about 0.4 mm to about 0.8 mm in some embodiments. The length of the implantable medical device can vary, but is generally about 1 mm to about 250 mm, about 2 mm to about 200 mm in some embodiments, about 10 mm to about 150 mm in some embodiments, and about 20 mm to about 100 mm in some embodiments.

[0074] IV. Use of the device

[0075] Implantable devices can effectively release antibodies over a long period of time as described above. Of course, the actual dosage level of the delivered antibody will vary according to the specific antibody used and the time period of its expected release. The dosage level is usually high enough to provide a therapeutically effective amount of antibodies that produce the desired treatment results, that is, the level or amount of the symptoms of the condition of the subject being administered that is effectively reduced or slowed down. More specifically, as used herein, the phrase "therapeutically effective amount" refers to the dosage of antibodies that cause detectable improvement in one or more symptoms of the disease, or the dosage of antibodies that inhibit, prevent, alleviate or delay the progression of the disease. The exact amount required will vary with factors such as the subject of treatment, the age and general condition of the subject to be delivered, the ability of the subject's immune system, the desired degree of action, the severity of the condition of the treatment, the specific antibodies selected, and the mode of administration of the composition. In one embodiment, for example, the therapeutically effective amount can be about 0.05 mg to about 5 mg, about 0.1 mg to about 4 mg in some embodiments, and about 0.5 mg to about 3 mg in some embodiments. The amount of the antibody contained in the individual dose can be expressed in milligrams of the drug per kilogram of patient body weight (i.e., mg / kg). For example, the antibody can be administered to a patient at a dosage of about 0.0001 mg / kg to about 10 mg / kg of the patient's body weight.

[0076] The device can be implanted subcutaneously, orally, mucosally, etc. using standard techniques. The delivery route can be intrapulmonary, intragastric, subcutaneous, intramuscular, or introduced into the central nervous system, intraperitoneal or intra-organ delivery. Implantable devices can be suitable for delivering antibodies to treat a variety of conditions, such as cancer, allergies, inflammation, immune-mediated diseases, metabolic diseases, eye disorders (e.g., angiogenic eye disorders), etc. The device can be placed in a tissue site in, on, adjacent to or near a patient's tumor, such as a pancreatic tumor, a biliary tumor, a gallbladder tumor, a liver tumor, a small intestinal tumor, a colon tumor, a brain tumor, a lung tumor, an eye tumor, etc.

[0077] In one embodiment, the implantable device can release antibodies that can treat cancer. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell carcinomas), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, testicular cancer, esophageal cancer, biliary tract tumors, and head and neck cancer. In a specific embodiment, an implantable device can deliver anti-HER2 antibodies to treat cancers that "overexpress" HER receptors. Such cancers include cancers in which the level of HER receptors (e.g., HER2) on the cell surface is significantly higher than that of non-cancerous cells of the same tissue type. This overexpression may be caused by gene amplification, or increased transcription or translation. If desired, treatment may include a combination of antibody preparations and chemotherapeutic agents. Combination administration includes co-administration or simultaneous administration using separate preparations or single pharmaceutical preparations and continuous administration in any order, wherein preferably there is a time period during which two (or all) active agents exert their biological activity simultaneously. Therefore, the chemotherapeutic agent can be administered before or after the antibody preparation according to the present invention is administered. In this embodiment, the time between at least one administration of the chemotherapeutic agent and at least one administration of the antibody preparation according to the present invention is preferably about 1 month or shorter, most preferably about 2 weeks or shorter. Alternatively, the chemotherapeutic agent and the antibody preparation can be administered to the patient simultaneously with a single preparation or a separate preparation.

[0078] The implantable device may also be useful for treating angiogenic eye disorders, including any eye disease caused by or associated with blood vessel growth or proliferation or vascular leakage. Non-limiting examples of angiogenic eye disorders that may be treated using the methods of the invention include age-related macular degeneration (e.g., wet AMD, exudative AMD, etc.), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO; e.g., macular edema following CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV; e.g., myopic CNV), iris neovascularization, neovascular glaucoma, post-glaucoma fibrosis, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, and diabetic retinopathy.

[0079] It is known to those skilled in the art that the device of the present invention can be implanted into the patient's eye in a different manner. For example, the device can be inserted into the anterior segment (the anterior chamber between the posterior surface of the cornea and the iris and / or the posterior chamber between the iris and the anterior surface of the vitreous body), the posterior segment (e.g., the anterior transparent membrane, the vitreous body, the retina, the choroid, etc.), the suprachoroidal space, or a combination thereof. When treating inflammatory eye conditions (e.g., uveitis, infectious corneal ulcers, endophthalmitis, keratitis, conjunctivitis, and thyroid eye disease), it is generally desired that the therapeutic agent be delivered to the posterior segment. In order to avoid having to pass through the blood-aqueous barrier, the implantable device can be directly inserted into the posterior segment, such as into the vitreous body ("intravitreal"). Intravitreal injection techniques are well known in the art, and can include, for example, using a hollow needle, through which the implant passes. The needle can have a small diameter size (e.g., 18 to 30 gauge needles) so that the incision is self-sealing, and implantation is performed in a closed chamber. A self-sealing incision may also be formed using a conventional "tunnel" procedure, in which a scraper-shaped scalpel is used to form a generally inverted V-shaped incision on the cornea. In a preferred embodiment, the instrument used to form the incision in the cornea remains in place (i.e., extends through the corneal incision) during the procedure and is not removed until after implantation. Such an incision-forming instrument may be used to place an ocular implant, or may be coupled with a delivery instrument to allow implantation through the same incision without removing the incision-forming instrument. Of course, in other embodiments, various surgical instruments may be passed through one or more corneal incisions multiple times.

[0080] The implantable device can be placed in the desired position in the eye according to a surgical procedure (e.g., a procedure known in the art). For example, the implantable device can be inserted into the suprachoroidal space by a sclerotomy. In this operation, the sclera is cut to expose the suprachoroidal space. The implantable device can then be positioned and inserted on both sides of the incision. Alternatively, a partial-thickness scleral trap-door can be made on the suprachoroidal space or an avascular area of ​​the eye. The implantable device can then be inserted and the scleral flap can be sutured back in place to fix the implant. Alternatively, the implantable device can be inserted so as to communicate directly with the vitreous cavity. To this end, a partial-thickness scleral trap-door is cut on an avascular area (e.g., the pars plana) to remove the eyeball wall. A hole (or multiple holes) is made at the bottom of the scleral bed to communicate with the bottom of the vitreous body through the pars plana of the ciliary body. The implantable device is placed above the hole in the scleral bed and the trap-door is sutured back in place. This placement of the implantable device will enable the drug to diffuse rapidly into the vitreous body and intraocular structures.

[0081] If necessary, the implantable device can be sealed in a package (e.g., a sterile blister package) before use. As known in the art, the material and method of the sealed package can vary. In one embodiment, for example, the package can include a substrate, and the substrate includes any number of layers required to achieve the desired level of protective performance, such as 1 or more layers, 1 to 4 layers in some embodiments, and 1 to 3 layers in some embodiments. Typically, the substrate includes a polymer film, such as those formed by polyolefins (e.g., ethylene copolymers, propylene copolymers, propylene homopolymers, etc.), polyesters (e.g., polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), vinyl chloride polymers, vinyl chloridine polymers, ionomers, etc., and combinations thereof. One or more plates of the film can be, for example, sealed together (e.g., heat-sealed) at the peripheral edge to form a cavity, in which the device can be stored. For example, a single film can be folded at one or more points and sealed along its periphery to define the cavity in which the device is located. To use the device, the package can be opened, for example, by breaking the seal, and the device is then taken out and implanted in the patient.

[0082] The present invention may be better understood through the following examples.

[0083] Test Method

[0084] Drug release: The release of drug preparations (e.g., lysozyme) can be measured using in vitro methods. More specifically, a sample of an implantable device can be placed in 150 ml of an aqueous PBS buffer solution. The solution is sealed in a stoppered centrifuge tube. The flask is then placed in a temperature-controlled incubator and continuously shaken at 100 rpm. A temperature of 37°C is maintained during the release experiment to simulate in vivo conditions. Samples are taken regularly by completely replacing the aqueous buffer solution. The concentration of the antibody in the solution can be determined by UV / Vis absorption spectroscopy using a Cary 3500 beam splitter. Based on this data, the amount of antibody released per sampling interval (micrograms / day) can be calculated and plotted over time (days). In addition, the cumulative release rate of the antibody can be calculated as a percentage by dividing the amount of antibody released per sampling interval by the total amount of antibody initially present and then multiplying that number by 100. The percentage is then plotted over time (days).

[0085] Examples 1 to 3

[0086] Rod-shaped monolithic implants containing human plasma-derived IgG antibodies were produced by extrusion. For Example 1, the device contained 60 wt.% 4030AC and 40 wt.% IgG antibody. For Example 2, the device contained 50 wt.% 4030AC and 50 wt.% IgG antibody. For Example 3, the device contained 55 wt.% 4030AC and 45wt.% IgG antibody. The devices of Examples 1 to 3 were formed by melt extruding the components using an 11 mm twin screw extruder. Extrusion was accomplished using a screw speed of 50 rpm, with the barrel temperature set to achieve a nominal melt temperature of 60°C. The rods were 3.5 mm in diameter and cut into 3 cm lengths for elution testing. The release of IgG from the rods was measured in PBS buffer in a shaking incubator maintained at 37°C. The buffer was regularly replaced with fresh buffer, and the removed buffer was characterized using UV-Vis absorption spectroscopy to measure the concentration of released IgG antibodies. Figure 1 The resulting cumulative release rate (%) over 160 days is shown. Figure 4 The elution data for Example 1 is shown as total mass per unit surface area of ​​the sample. For Example 1, only about 30% of the total antibody was eluted in 160 days. For Example 2, nearly 60% of the total antibody was released in less than 20 days. For Example 3, about 25% of the antibody was eluted around day 21. The results for Example 1 are shown in Table 1 below.

[0087] The results of Example 2 are shown in Table 2 below. The results of Example 3 are shown in Table 3 below.

[0088] Table 1

[0089]

[0090] Table 2

[0091]

[0092] Table 3

[0093]

[0094] Example 4

[0095] The pharmaceutical formulation is initially formed from the following components in Table 4:

[0096] Table 4

[0097] Components Concentration (wt.%) Trastuzumab biosimilar (Syd Labs) 51.3 Trehalose 46.6 L-Histidine hydrochloride monohydrate 1.2 L-Histidine 0.7 Sorbitan monolaurate 0.2

[0098] To form the formulation, the trastuzumab biosimilar was first lyophilized from an aqueous buffer and then additional excipients were mixed with the antibody to form a solid powder. After formation, the powder was incorporated into an implantable device such that the resulting device contained 55 wt.% of 4030AC and 45wt.% powder. The device was formed by melt extruding the components using an 11mm twin-screw extruder. Extrusion was accomplished using a screw speed of 55rpm with the barrel temperature set to achieve a nominal melt temperature of 60°C. The rods were 3mm in diameter and were cut into 1cm lengths for elution testing. The release of trastuzumab biosimilars from the rods was measured in PBS buffer in a shaking incubator maintained at 37°C. The buffer was replaced regularly with fresh buffer and the removed buffer was characterized using UV-Vis absorption spectroscopy to measure the concentration of released trastuzumab antibodies. Figure 3 The resulting cumulative release rate (%) over 35 days is shown. Approximately 40% of the total antibody was released over 35 days.

[0099] The results of Example 4 are shown in Table 5 below.

[0100] Table 5

[0101]

[0102] Examples 5 to 6

[0103] A rod-shaped monolithic implant containing lysozyme was produced by extrusion. For Example 5, the device contained 60 wt.% 4030AC and 40 wt.% lysozyme. For Example 6, the device contained 45 wt.% 4030AC and 60wt.% lysozyme. Devices of both examples were formed by melt extruding the components using an 11 mm twin screw extruder. Extrusion was accomplished using a screw speed of 100 rpm with the barrel temperature set to achieve a nominal melt temperature of 75°C. The rods were 3.5 mm in diameter and were cut into 3 cm lengths for elution testing. The release of lysozyme from the rods was measured in PBS buffer in a shaking incubator maintained at 37°C. The buffer was replaced regularly with fresh buffer and the removed buffer was characterized using UV-Vis absorption spectroscopy to measure the concentration of released lysozyme. Figure 4 The resulting cumulative release rate (%) over 9 days is shown. For Example 5, about 50% of the total lysozyme was eluted in 9 days. For Example 6, more than 60% of the total lysozyme was released in less than 9 days. The results of Examples 5 to 6 are shown in Tables 6 and 7 below.

[0104] Table 6

[0105]

[0106] Table 7

[0107]

[0108] Examples 7 to 11

[0109] To characterize the protein after drug release, freshly prepared human plasma derived IgG antibody solutions and solutions collected at selected time points during the elution study described in Example 1 were characterized by size exclusion chromatography (SEC) using an HPLC system equipped with an Agilent AdvanceBio SEC column. Phosphate buffer (0.15 M; pH 7.0) was used as the elution medium and the flow rate was maintained at 1 mL / min. The detection wavelength was set to 280 nm. These samples are described in the table below.

[0110] Example describe Example 7 Freshly prepared IgG solution (1 mg / ml) Example 8 Solution collected at the 6th day in Example 1 Example 9 Solution collected at the 21st day in Example 1 Example 10 Solution collected at the 86th day in Example 1 Embodiment 11 Solution collected at the 160th day in Example 1

[0111] Figures 5 to 9 The freshly prepared solution (Example 7) showed a large protein monomer peak (8 min retention time) and a smaller protein dimer peak (7 min retention time) (see Figure 5 At the 6th and 21st day time points (Examples 8 and 9), the collected solutions showed a clear monomer peak and a small dimer peak (see Figures 6 to 7). At the 86th day (Example 10) and 160th day (Example 11) time points, significant degradation of the protein was evident based on the introduction of a new peak at a higher retention time (9 minutes retention time). In addition, some protein aggregation was detected in Example 10 based on the introduction of a small peak at a lower retention time (5.5 minutes). (See Figures 8 to 9 ).

[0112] Those of ordinary skill in the art can practice these and other modifications and variations of the present invention without departing from the spirit and scope of the present invention. In addition, it should be understood that the various aspects of each embodiment can be interchanged in whole or in part. In addition, those of ordinary skill in the art will understand that the foregoing description is only by way of example and is not intended to limit the present invention further described in the appended claims.

Claims

1. A monolithic implantable device for delivering an antibody, the implantable device comprising a polymer matrix having dispersed therein a pharmaceutical formulation comprising one or more therapeutic agents and optionally one or more excipients, wherein the therapeutic agent comprises an antibody, the polymer matrix comprises a hydrophobic polymer, wherein the device exhibits a cumulative release rate of the antibody on a weight basis of about 20% to about 60% over a period of 35 days.

2. The monolithic implantable device of claim 1, wherein the weight ratio of the drug formulation to the polymer matrix is ​​from about 0.7 to about 1.

3. The monolithic implantable device of claim 2, wherein the weight ratio of the therapeutic agent to the polymer matrix is ​​from about 0.7 to about 1.

4. The monolithic implantable device of claim 2, wherein the weight ratio of the therapeutic agent to the polymer matrix is ​​from about 0.3 to about 1.

5. The monolithic implantable device of any of the preceding claims, wherein the drug formulation comprises about 30 wt.% to about 50 wt.% of the device and the polymer matrix comprises about 50 wt.% to about 70 wt.% of the device.

6. The monolithic implantable device of any of the preceding claims, wherein the device exhibits a cumulative release rate of the antibody on a weight basis of about 10% to about 55% over a period of 15 days.

7. The monolithic implantable device of any of the preceding claims, wherein the hydrophobic polymer is a copolymer comprising a polar monomer and an olefin monomer.

8. The monolithic implantable device of any of the preceding claims, wherein the polar monomer is present in an amount of 10 wt.% to about 60 wt.% of the copolymer.

9. A monolithic implantable device according to any of the preceding claims, wherein the hydrophobic polymer has a melt flow index of about 0.2 g / 10 min to about 100 g / 10 min as measured at a temperature of 190° C. and a load of 2.16 kg according to ASTM D1238-20, and / or a melting temperature of about 20° C. to about 70° C. as measured according to ASTM D3418-21.

10. The monolithic implantable device of any preceding claim, wherein the hydrophobic polymer comprises ethylene vinyl acetate copolymer.

11. The monolithic implantable device of any preceding claim, wherein the hydrophobic polymer comprises the entire polymer matrix.

12. The unitary implantable device of any preceding claim, wherein the antibody comprises a monoclonal antibody.

13. The monolithic implantable device of claim 12, wherein the monoclonal antibody comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-HER2 antibody, an anti-VEGF antibody, or a combination thereof.

14. The monolithic implantable device of claim 13, wherein the anti-HER2 antibody comprises trastuzumab, pertuzumab, makituximab, or an antigen-binding variant thereof.

15. The monolithic implantable device of claim 13, wherein the anti-VEGF antibody comprises bevacizumab, ranibizumab, or an antigen-binding variant thereof.

16. The monolithic implantable device of any preceding claim, wherein the drug formulation comprises one or more excipients.

17. The monolithic implantable device of claim 16, wherein the excipient comprises a buffer.

18. The monolithic implantable device of claim 17, wherein the buffer comprises a histidine buffer.

19. The monolithic implantable device of claim 16, wherein the excipient comprises a carbohydrate.

20. The monolithic implantable device of claim 19, wherein the sugar comprises glucose, fructose, galactose, ribose, deoxyribose, sucrose, lactose, maltose, trehalose, xylitol, sorbitol, mannitol, maltitol, erythritol, dulcitol, inositol, lactitol, or a combination thereof.

21. The monolithic implantable device of claim 16, wherein the excipient comprises a surfactant.

22. The monolithic implantable device of claim 21, wherein the surfactant comprises a sorbitan fatty acid ester modified with polyoxyethylene.

23. A monolithic implantable device according to any one of the preceding claims, wherein the formulation is in the form of a dehydrated particulate material.

24. A unitary implantable device according to any one of claims 1 to 23, wherein the device has a generally circular cross-sectional shape.

25. A unitary implantable device according to any one of claims 1 to 23, wherein the device is in the form of a cylinder.

26. The unitary implantable device of any of the preceding claims, wherein the device has a thickness of about 0.1 mm to about 10 mm and / or a length of about 1 mm to about 250 mm.

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