Complement antibody-drug conjugate

Abstract

This application provides antibody-drug synergistic compounds, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. The antibody-drug synergistic compounds may include antibodies such as anti-angiogenic antibodies or anti-VEGF antibodies conjugated to small molecule complement inhibitors by a linker, or anti-complement antibodies conjugated to small molecule inhibitors of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR by a linker. The linker conjugating the antibody and drug is hydrolyzable over time within the target eye, thereby allowing both the antibody and drug to exert their functions within the target eye. The compounds and compositions can confer superior efficacy compared to either the antibody or the drug alone due to the synergistic effect of the ADS compounds. Methods for treating age-related macular degeneration using ADS compounds and compositions are also provided.

Description

Technical Field

[0001] Priority Claim This application claims priority to U.S. Provisional Patent Application No. 63 / 469,775, filed May 30, 2023, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to antibody-drug synergistic effect compounds, compositions thereof, and methods of using such compounds.

Background Art

[0003] Background Age-related macular degeneration (AMD) is a disease that can cause central vision loss in people over 50 years old and is one of the most common causes of severe vision loss in this age group. There are mainly two types of AMD. In exudative AMD, abnormal blood vessels that grow behind the retina leak or bleed under the retina, resulting in accompanying central vision loss. For ophthalmic applications, for example, for the treatment of exudative AMD, anti-VEGF (vascular endothelial growth factor) agents have been used. These agents are delivered by injection into the eye.

[0004] Dry AMD occurs more slowly through the early, intermediate, and late stages. In dry AMD, the cells in the macula are destroyed over time. Currently, there is no treatment for early and intermediate dry AMD, and until recently, there was no treatment for dry AMD at all. Geographic atrophy (GA) is the final stage of dry AMD, and patients develop blind spots in the central vision and other vision loss. Complement cascade is thought to be involved in GA, and the complement inhibitor pegcetacoplan, delivered by injection, was recently approved as the first treatment for GA.

Summary of the Invention

[0005] Summary Anti-angiogenic strategies are effective treatments for ocular neovascular diseases such as exudative AMD (also known as wet AMD). While anti-VEGF agents have been used to treat exudative AMD, these therapies target only one of the possible pathways involved in the pathogenesis of exudative AMD. Although these drugs are effective, further improvements are needed for better treatment of exudative AMD. For example, targeting additional pathogenesis factors other than VEGF, longer injection intervals, and the need to treat treatment-resistant patients remain unresolved. Currently, there is no single treatment that targets multiple pathways, both neovascular and non-angiogenic, involved in the pathogenesis of exudative AMD. While it is possible to administer additional medications in addition to anti-VEGF agents, this requires additional intravitreal injections to the patient. Increasing the number of injections to the patient is undesirable because intravitreal injections can increase the risk of retinal detachment and infections that can lead to endophthalmitis. Furthermore, the need for frequent injections increases the treatment burden, reduces patient compliance, and can result in inadequate vision. Alternative treatment options for exudative AMD are needed, including therapies that can target multiple pathways that contribute to the disease's pathogenesis.

[0006] While new medications are available to treat end-stage dry AMD with GA, these are currently the only treatments for dry AMD, targeting only a single component of the complement pathway and only the end stages of the disease. Dry AMD needs more treatment options, including more choices that can provide high efficacy against the disease, and early treatment options that target earlier stages of the disease.

[0007] The complement pathway is thought to play a role in the pathogenesis of AMD and is involved in the end-stage outcomes of both dry AMD-GA and exudative AMD. Therefore, inhibiting the complement pathway may be beneficial in preserving vision and halting disease progression in both dry and exudative AMD. To date, there are no approved ophthalmic therapies that inhibit both the angiogenic pathway or VEGF pathway and the complement pathway with a single therapeutic agent.

[0008] Furthermore, clinical trials of complement inhibitors such as pegcetacoplan have shown an increased risk of progression to exudative AMD, a progression thought to be a direct effect of complement inhibition. Inhibiting both complement and VEGF may help minimize or prevent this vision-impairing side effect.

[0009] This disclosure relates to antibody-drug synergies, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. An antibody-drug synergy may comprise: an antibody, such as a first target in the subject, e.g., a classical antibody or a modified or engineered biological molecule that blocks a first pathological pathway; a drug or therapeutic agent, such as a molecular agent or small molecule agent that blocks a second pathological pathway or a second component of the first pathological pathway, e.g., a first or second target in the subject; and a linker that conjugates the antibody and the drug, which is hydrolyzable over time in the subject, e.g., in the eye of the subject, so that both the antibody and the drug exert their functions simultaneously. In some cases, the first target may be any of the angiogenesis-related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR. In some cases, the second target may be complement pathway targets such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. In some cases, the first target may be complement pathway targets such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. In some cases, the second target may be any angiogenesis-related target such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR. In some cases, the first target may be any angiogenesis-related target such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR, and the second target may be a complement pathway target such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. In some cases, the first target may be complement pathway targets such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46, and the second target may be any of the angiogenesis-related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR. In some cases, the compounds and compositions can confer superior efficacy to either the antibody or the drug alone through the synergistic action of the ADS compounds.

[0010] In another aspect, the disclosure also relates to synergistic bispecific antibody compounds, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. Synergistic bispecific antibody compounds may include a single antibody, e.g., a classical antibody or a modified biological molecule, that blocks a first target in a target such as VEGF or the angiogenic pathway, and a second target in a target such as the complement pathway. Thus, in some embodiments, a bispecific antibody may include an antibody designed to block a first target which is one of the angiogenesis-related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR, and also designed to block a second target which is a complement pathway target such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. In some cases, the compounds and compositions can confer superior efficacy to either antibody alone due to the synergistic effect of the bispecific antibody compounds.

[0011] In one situation, Anti-complement antibodies or manipulated biological molecules; Small molecules selected from multi-kinase inhibitors (MKIs) and anti-angiogenic inhibitors; and A linker that links antibodies to small molecules and is capable of cleaving in the mammalian eye environment. Compounds containing the above are described herein.

[0012] In this and other embodiments, the compound may optionally have the following characteristics: The anti-complement antibody or engineered biological molecule can be selected from anti-C3 antibody, anti-C3b antibody, anti-factor B antibody, anti-factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and anti-factor H antibody. The anti-complement antibody or engineered biological molecule can be selected from pegcetacoplan, eculizumab, ravulizumab, pegcetacoplan, and abasincaptado pegol. MKI includes canertinib, clenoranib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lenvatinib, linifanib, motesanib, neratinib, quizartinib, tandutinib, civantinib, cibozanib, batalanib, cejiranib, trametinib, dabrafenib, vemurafenib, and palbosic. The following can be selected: rib, amvatinib, dasatinib, foretinib, golbatinib, imatinib, nilotinib, pazopanib, crizotinib, sunitinib, sorafenib, axitinib, ponatinib, ruxolitinib, vandetanib, cabozantinib, afatinib, ibrutinib, nintedanib, regorafenib, idelalisib, ceritinib, LY2874455, and SU5402, or their pharmaceutically acceptable salts, or combinations thereof. The anti-angiogenic inhibitor can be selected from squalamine or corticosteroids. The mammalian ocular environment can be selected from vitreous fluid, a portion of the posterior segment, or ocular tissue. The linker can be selected from those containing esters, amides, carbamates, carbonates, imines, ethers, phosphates, ureas, sulfonamides, or hydrazone bonds.

[0013] In some situations, the linker can optionally It could be TIFF2026521989000001.tif16128, In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkylheteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0014] In these and other embodiments, the compound may optionally have the following further features: The antibody or engineered biological molecule can be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. The PEG moiety may be -(CH2-CH2-O-)n-, where n may be 5-30 or 10-15. A linker can link a small molecule drug to the antibody or engineered biological molecule via the PEG moiety. The linker may comprise a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM). The linker may comprise PEG linked to an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or hydrazone linkage. The antibody or engineered biological molecule may be an anti-C3 antibody or engineered biological molecule, or an anti-C5 antibody or engineered biological molecule. The small molecule can be selected from axitinib, cedilanib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, batalanib, LY2874455, and SU5402. The small molecule may be axitinib. In some cases, the antibody or engineered biomolecule may be pegcetacoplan or abasincaptado pegol, and the small molecule may be axitinib.

[0015] In another context, compounds comprising a small molecule complement inhibitor; an antibody or engineered biological molecule which is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a linker which links the antibody or engineered biological molecule to a small molecule and is cleavable in the mammalian eye environment are described herein.

[0016] In this and other embodiments, the compound may optionally have the following characteristics: The complement inhibitor can be selected from C3 inhibitors, C3b inhibitors, C5 inhibitors, C5a inhibitors, C5b inhibitors, factor B inhibitors, factor D inhibitors, factor H inhibitors, and CD46 inhibitors. The antibody or engineered biomolecule may be a VEGF-A antibody or an engineered biomolecule. The antibody or engineered biomolecule can be selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and convercept. The mammalian ocular environment can be selected from vitreous fluid, a portion of the posterior segment, ocular tissue, or ocular cells. The linker can be selected from those containing esters, amides, carbamates, carbonates, imines, ethers, phosphates, urea, sulfonamides, or hydrazone bonds.

[0017] In some situations, the linker can optionally It could be TIFF2026521989000002.tif16128, In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkylheteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0018] In these and other embodiments, the compound may optionally have the following further features: The antibody or engineered biological molecule can be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. The PEG moiety may be -(CH2-CH2-O-)n-, where n may be 5-30 or 10-15. A linker may be used to link a small molecule drug to the antibody or engineered biological molecule via the PEG moiety. The complement inhibitor may be selected from C3 inhibitors, C3b inhibitors, C5 inhibitors, C5a inhibitors, and C5b inhibitors. The complement inhibitor may be avacopan or pegcetacoplan. The antibody may be aflibercept.

[0019] In another aspect, a first antigen-binding site that binds to a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a second antigen-binding site that binds to at least a portion of a complement protein selected from factor B, factor D, C5, C5a, CD46, and factor H are described herein as bispecific antibodies or engineered biological molecular compounds.

[0020] In this and other aspects, the compound can optionally have the following characteristics. The first antigen-binding site can bind to at least a portion of VEGF-A. The antibody or engineered biological molecule can be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. The PEG moiety can be -(CH2-CH2-O-)n-, where n can be from 5 to 30 or n can be from 10 to 15.

[0021] In another aspect, a composition comprising any of the compounds described herein and above is described herein.

[0022] In this and other aspects, the composition can optionally have the following characteristics. The composition can be an injectable ophthalmic formulation.

[0023] In another aspect, a method for treating a disease is described herein that includes the step of administering any of the compounds or compositions described herein or above to a subject.

[0024] In these and other aspects of the methods described herein, the method can optionally have the following features. The linker can be hydrolyzed over time in the subject such that both the antibody and the small molecule can perform their functions in the subject. The disease can be selected from graft-versus-host disease, cancer, tumor, or nephrosis. The method can be a method for treating an eye disease, comprising administering to the eye of a subject any of the compounds or compositions described herein. The eye disease can be selected from age-related macular degeneration (AMD), graft-versus-host disease, retinal hemangioblastoma, uveal melanoma, corneal neovascularization, ocular surface tumor, and retinal astrocytic hamartoma. The eye disease can be age-related macular degeneration (AMD). AMD can be exudative AMD. AMD can be dry AMD. AMD can be early or intermediate AMD. AMD can be late AMD. Late AMD can be exudative AMD, AMD with geographic atrophy (GA), or a combination thereof. The eye disease can be geographic atrophy (GA) secondary to AMD. The subject can experience a decrease in the average rate of change of the square root of the GA area after administration of the compound or composition. The subject can experience a delay or cessation of GA growth. Administration can include delivering or injecting to the eye of the subject via intravitreal, intracameral, subretinal, or suprachoroidal delivery.

[0025] In some cases described herein, the compounds, compositions, and methods provided herein can offer several advantages. First, in some cases of the compounds, compositions, and methods provided herein, a synergistic and enhanced efficacy in the treatment of eye diseases in a subject, such as AMD including exudative AMD and dry AMD, can be provided. In some cases, the antibody and the drug can perform their functions simultaneously, and due to the synergistic effect of the ADS compound, the ADS compound confers superior efficacy compared to either the antibody or the drug alone.

[0026] Secondly, in some cases of the compounds, compositions, and methods provided herein, the compounds can provide an improved treatment for dry AMD with GA by reducing side effects and conversion to exudative AMD. Clinical trials of complement inhibitors for the treatment of AMD with GA, such as Pegcetacoplan, have shown an increased risk of conversion to exudative AMD. While not bound by theory, this conversion to exudative AMD is thought to be a direct effect of complement inhibition. Furthermore, inhibiting both complement and VEGF is thought to minimize or prevent this vision-threatening side effect. Therefore, by achieving such dual inhibition in a single treatment, it is possible to provide a treatment for AMD with GA that prevents or mitigates the potential side effect of conversion to exudative AMD.

[0027] Thirdly, in some cases, the compounds, compositions, and methods provided herein can provide a single therapeutic agent that targets multiple pathways involved in the pathogenesis of AMD. Such a single therapeutic agent not only has the potential to improve outcomes by targeting multiple pathways, but the single therapeutic agent approach is also clearly advantageous over the method of injecting two different agents into the eye separately, which may increase the risk of infection and the burden on the patient.

[0028] Fourth, in some cases, linked compounds can provide long-lasting therapeutic activity after injection. In some cases, linker cleavage occurs slowly over time, thereby releasing the therapeutic agent and enabling a longer duration of treatment by slowly cleaving the drugs together. This can be beneficial as it reduces the risk of injection-induced infection and alleviates the burden on the patient by allowing for longer injection intervals.

[0029] Fifth, in some cases, the compounds, compositions, and methods described herein can avoid the potential side effects of small molecule inhibitors such as multi-kinase inhibitors or complement inhibitors by ensuring local delivery based on the inertness of the ADS compound when intact and by exhibiting activity only when the linker is cleaved at the desired site or tissue.

[0030] Sixth, the antibody portion of the ADS compound can act both as a carrier for small molecules and as a therapeutic agent due to its own activity. The carrier activity of the antibody portion can further offer the benefit of overcoming the difficulties in formulating small molecules for delivery to the posterior segment of the eye, such as intravitreous administration.

[0031] Other features and advantages of this application will become apparent from the following detailed description and drawings, as well as from the claims. [Modes for carrying out the invention]

[0032] Detailed explanation This specification provides antibody-drug synergy compounds, compositions, and methods for using the compounds or compositions.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. While methods and materials for use in this application are described herein, other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not limiting. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated by reference in their entirety. In case of any conflict, this specification, including its definitions, shall prevail.

[0034] As used herein, the terms “individual,” “patient,” or “subject” are interchangeable and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. In some embodiments, a human subject may be of any age, for example, from 0 to 100 years of age.

[0035] As used herein, the terms “effective dose” or “therapeutic dose” refer to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human, as sought by researchers, veterinarians, physicians, or other clinicians.

[0036] As used herein, the terms “to treat” or “to cure” mean 1) inhibiting a disease, for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., stopping the further progression of the pathology and / or symptoms), or 2) relieving a disease, for example, relieving a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms).

[0037] Antibody-drug synergy (ADS) technology is a concept that utilizes the synergistic effect between antibodies and small molecule drugs to treat various diseases, such as eye diseases. In this technology, ADS compounds are formed by covalently linking a small molecule drug to an antibody drug via a linker. This differs from antibody-drug conjugate (ADC) technology, which is focused on oncology, in three key ways: 1) In ADS technology, the antibody is used as a disease modifier, whereas in ADC technology, the antibody is merely a carrier for targeting the small molecule drug to cancer cells. Therefore, in ADS, the antibody and small molecule have a synergistic effect on the target disease, whereas in ADC, the antibody and small molecule do not. 2) In the disclosed method, the linker is cleaved outside the cell (e.g., in the vitreous humor of the eye) to release the small molecule drug, whereas in ADC technology, the linker is cleaved inside the cancer cell or not cleaved at all. 3) ADS technology also serves as a carrier that slowly breaks down the linker to release small molecule drugs at the injection site, resulting in the long-term effects of the small molecule drugs, whereas in ADC, the antibody does not perform this function. Although this application focuses on ocular diseases to illustrate the concept, the disclosed method can be used for any disease in which topical drug administration is an appropriate treatment.

[0038] Ocular neovascularization is a disease of the eye characterized by abnormal angiogenesis (vascular growth) and vascular leakage. Examples include exudative (wet) age-related macular degeneration (AMD), diabetic macular edema, retinal vein occlusion, diabetic retinopathy, corneal neovascularization, and pterygium.

[0039] Anti-angiogenic biological agents can be an effective treatment for ocular neovascular diseases such as exudative AMD. Successful examples include bevacizumab (off-label use), ranibizumab, aflibercept, brolucizumab, and convercept, all of which are VEGF-A neutralizing biological agents (Rosenfeld et al 2006, Martin et al 2011, Stewart et al 2012). Despite the success of these biological agents, the need for better treatment of exudative AMD remains unmet. Anti-VEGF-A alone is insufficient to achieve the desired outcome of exudative AMD, which is regression of neovascularization. Another need is to treat patients for whom VEGF-A inhibition has become ineffective (Jo et al 2006). To address these unmet needs, new strategies are being tested clinically. For example, multitarget small molecule agents are being tested as topical formulations (Csaky et al 2015). However, delivering small molecules to the retina via local pathways has proven difficult, and intravitreal formulations present many challenges. Furthermore, other signaling pathways, such as the complement pathway, are also involved in the pathogenesis of AMD. These pathways may influence the early, middle, or late stages of the disease, or the severity of the disease. The compounds and methods disclosed herein employ novel methods that simultaneously target multiple causative factors, such as the aforementioned VEGF or anti-angiogenic signaling pathways and the complement signaling pathway.

[0040] ADS technology can be used as a novel method to treat ocular neovascular diseases such as exudative AMD, dry AMD, or GA secondary to AMD. This technology utilizes the synergistic effect between an antibody and a small molecule drug to achieve a better effect than either single component alone. A technology called antibody-drug conjugates (ADCs) has been used in cancer treatment. This technology involves linking an anticancer drug, usually a cytotoxic agent, to an antibody that induces the drug in cancer cells, giving it some selectivity. The antibody used in ADC platforms simply acts as a carrier to bind to target cancer cells and has no therapeutic effect. ADC approaches are used to improve the safety or pharmacokinetic profiles of anticancer drugs (Kim et al 2015, Peters et al 2015), and the linker in the ADC is designed to either cleave within the cell to release the anticancer drug or remain uncleaved at all. The ADS platform method differs from ADC technology in three key ways. Unlike ADC technology, where the antibody is an inert carrier, in ADS method the antibody itself is a therapeutic agent designed to have a synergistic therapeutic effect with the small molecule drug linked to it. Secondly, the linker in this disclosure is designed to be hydrolyzed in the vitreous fluid or other ocular tissue, rather than within cancer cells. Thirdly, ADS technology also serves as a carrier that slowly breaks down the linker to release the small molecule drug at the injection site, resulting in a long-lasting effect of the small molecule drug, whereas in ADC, the antibody does not perform this function. In addition to these three differences, the method in this disclosure is designed for ocular or other local injections, rather than systemic cancer treatment. ADS technology makes it possible to modify multiple ocular targets to obtain a synergistic therapeutic effect. In addition to being a therapeutic agent, the antibody in the method in this disclosure can also act as a carrier that facilitates the sustained delivery of small molecule drugs to the vitreous humor, which has been difficult to achieve until now.

[0041] The antibodies in the compounds, compositions, and methods described herein may be classical antibodies, antibody hybrid fusions, or any other biological molecules or engineered biological molecules designed to block any of the angiogenesis-related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF, and FGFR, or any of the complement pathway targets such as C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. The small molecules in the compounds, compositions, and methods described herein may be multi-kinase inhibitors, angiogenesis inhibitors, or complement inhibitors.

[0042] In some embodiments, ADS compounds are provided that comprise an anti-complement antibody or a manipulated biological molecule; a small molecule such as a multi-kinase inhibitor (MKI) or an anti-angiogenic inhibitor; and a linker that ligates the antibody to the small molecule and is cleavable in the mammalian ocular environment. The linker, upon entering the target ocular environment, such as in the vitreous fluid, may be hydrolyzed over time in the target, thereby allowing both the antibody and the drug to exert their functions simultaneously. In some cases, these compounds can confer superior efficacy to either the antibody or the drug alone due to the synergistic effect of the ADS compounds.

[0043] In some embodiments, the antibody or engineered biological molecule is an anti-complement antibody or engineered biological molecule. In some embodiments of the compounds, compositions, and methods, the antibody may be a classical antibody, an antibody hybrid fusion, or any other biological molecule designed to block any of the complement-related targets. Non-limiting examples of complement pathway targets for the ADS compounds described herein include C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. Non-limiting examples of anti-C3 antibodies useful in the compounds and methods described herein include pegcetacoplan. Non-limiting examples of anti-C5 antibodies or engineered biological molecules useful in the compounds and methods described herein include eculizumab, ravulizumab, and abasincaptado pegol. Non-limiting examples of anti-C5a antibodies or engineered biological molecules include clobarimab, zircoplan, and pozerimab. In some cases described herein, the antibody may be an antibody mimetic or a chemoantibody such as an RNA aptamer. Non-limiting examples of antibody mimetic or chemoantibodies useful as antibody components of ADS compounds in some embodiments described herein include abasin-captado pegol. In some embodiments, the antibody component may be an engineered biological molecule such as pegcetacoplan. In some embodiments, the antibody may be pegylated.

[0044] In some embodiments, the small molecule agent may be a multikinase inhibitor against one or more tyrosine kinases. Examples of tyrosine kinase inhibitors include canertinib, clenolanib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lenvatinib, linifanib, motesanib, neratinib, quizartinib, tandutinib, tivantinib, tivozanib, batalanib, cejiranib, trametinib, dabrafenib, vemurafenib, palbociclib, amvatinib, dasatinib, foretinib, and golbatinib. Examples include imatinib, nilotinib, pazopanib, crizotinib, sunitinib, sorafenib, axitinib, ponatinib, ruxolitinib, vandetanib, cabozantinib, afatinib, ibrutinib, nintedanib, regorafenib, idelalisib, ceritinib, LY2874455, SU5402, and any other agents or combinations thereof that inhibit VEGFR, PDGFR, and FGFR. In some embodiments, the small molecule agent may be another type of anti-angiogenic inhibitor, such as squalamine or a corticosteroid.

[0045] In some embodiments, an ADS compound is provided comprising: an antibody that is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; a small molecule complement inhibitor; and a linker that links the antibody to a small molecule and is cleavable in the mammalian ocular environment. The linker, upon entering the target ocular environment, such as in the vitreous fluid, may be hydrolyzed over time in the target, thereby allowing both the antibody and the drug to exert their functions simultaneously. In some cases, these compounds can confer superior efficacy to either the antibody or the drug alone due to the synergistic effect of the ADS compounds.

[0046] In some embodiments, the antibody is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR. The antibody in some embodiments of the compounds, compositions, and methods described herein may be a classical antibody, an antibody hybrid fusion, or any other biological molecule designed to block any of VEGF, VEGFR, PDGF, PDGFR, FGF, FGFR, or other anti-angiogenesis-related targets. Non-limiting examples of biological drugs designed to block angiogenesis-related targets include bevacizumab, ranibizumab, ramucirumab, aflibercept, brolucizumab, and convercept.

[0047] Furthermore, any anti-angiogenic protein drugs (e.g., those in clinical trials but not yet approved by the FDA, or newly discovered ones) may also be included. Non-limiting examples include anti-VEGF / anti-PDGF Darpin (Allergan), sevacizumab (anti-VEGF, Jiangsu Simcere Pharmaceutical), TK001 (anti-VEGF, Jiangsu T-Mab Biopharma), tanibirumab (anti-VEGFR2, PharmAbcine), LMG324 (anti-VEGF, Alcon / Norvatis), BCD-021 (bevacizumab biosimilar, Biocad), IMC-3G3 (anti-PDGFR, ImClone LLC), MEDI-575 (anti-PDGFR, Medimmune LLC), TRC105 (anti-endoglin antibody, NCI), Fovista (anti-PDGF, Opthotech), and any other inhibitors of VEGF, PDGF, VEGFR, or PDGFR. In some cases, the antibodies in the methods of this disclosure may be single-target, dual-target (e.g., bispecific), or multi-target biopharmaceuticals. In some embodiments, the compounds described herein can be used to treat diseases other than those of the eye. In some embodiments, the antibodies or engineered biological molecules may be BAFF inhibitors, anti-CD20 antibodies, RANKL inhibitors, IL-12 and IL-23 antagonists, IL-1 antagonists, IL-1β antagonists, TNF inhibitors, TNFα inhibitors, complement inhibitors, complement C5 inhibitors, IL-6 receptor inhibitors, cell adhesion molecule α4-integrin inhibitors, T cell modulators, CD1 1a conjugates or blockers, anti-IgE antibodies, competitive IL-2 antagonists, glycoprotein IIb / IIIa receptor antagonists, or combinations thereof. In some embodiments, the antibody or engineered biological molecule may be selected from bevacizumab, ranibizumab, brolucizumab, aflibercept, convercept, aveiximab, adalimumab, basiliximab, belimumab, canakinumab, certolizumab or certolizumab pegol, denosumab, eculizumab, efalizumab, golimumab, infliximab, natalizumab, omalizumab, tocilizumab, ustekinumab, or a combination thereof.

[0048] Furthermore, in some cases, the antibody in the method of the present disclosure may be pegylated. In some embodiments, the antibody may be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. In some embodiments, the PEG moiety may be -(CH2-CH2-O-)n-, where n is 5 to 30 or n is 10 to 15. In some embodiments, a linker may link a small molecule drug to the antibody or engineered biological molecule via the PEG moiety.

[0049] In some cases, the compound may contain a small molecule complement inhibitor. Non-limiting examples of complement pathway targets for small molecule complement inhibitors of the ADS compounds described herein include C3, C3b, C5, C5a, C5b, factor B, factor D, factor H, and CD46. A non-limiting example of such a small molecule complement pathway inhibitor is avacopan. In some embodiments, the small molecule complement pathway inhibitor may be pegcetacopan. In some embodiments, the small molecule complement pathway inhibitor may be abasincaptadopegol.

[0050] In some embodiments, such as when the small molecule component is an angiogenesis inhibitor and the antibody component is an anti-complement antibody or a manipulated biological molecule, pegcetacoplan can act as an antibody component. In other embodiments, such as when the antibody component is an anti-angiogenic antibody or a manipulated biological molecule and the small molecule component is a complement inhibitor, pegcetacoplan can act as a small molecule component.

[0051] In some embodiments, such as when the small molecule component is an angiogenesis inhibitor and the antibody component is an anti-complement antibody or a manipulated biological molecule, abasin-captadopegol can act as an antibody component. In other embodiments, such as when the antibody component is an anti-angiogenic antibody or a manipulated biological molecule and the small molecule component is a complement inhibitor, abasin-captadopegol can act as a small molecule component.

[0052] In some embodiments of the compounds, compositions, and methods described herein, the linker may be any type of linker that can be cleaved in the mammalian ocular environment, for example, in the vitreous humor, part of the posterior segment, aqueous humor, sub-Tenon's capsule, cornea, conjunctiva, choroid, ocular tissue, ocular cells, or a combination thereof. As disclosed herein, the posterior segment may include all tissues at the back of the eye up to the retina. Examples of linkers that can be hydrolyzed intraocularly (and in other tissues) include esters, amides, carbamates, carbonates, imines, ethers, phosphates, ureas, sulfonamides, or hydrazone bonds. In some embodiments, the linker may be an ester, amide, carbamate, carbonate, imine, ether, phosphate, hydrazone, acetal, or hydrozone bond.

[0053] In some situations, Linker The filename is TIFF2026521989000003.tif16128. In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkylheteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0054] Linkers used in conventional ADC platforms are also included if they can be hydrolyzed in the ocular environment. These include hydrazones, disulfides, dipeptides, and β-glucuronides (Kim and Kim 2015, Peters and Brown 2015). In some embodiments, the linker may be selected to be cleaved in other target tissues such as joint tissue, muscle tissue, blood, skin, epithelial tissue, connective tissue, and nerve tissue. Furthermore, the linker may be a small molecule polymer conjugate. In some embodiments, the linker may include PEG linked to a small molecule complex. As a non-limiting example, the linker may include esters, amides, carbamates, carbonates, imines, ethers, phosphates, urea, sulfonamides, or PEG linked to a hydrazone linkage. In some embodiments, the linker may include a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM).

[0055] The hydrolysis rate of linkers can be designed to be fast, with a hydrolysis half-life of 1-60 minutes or 1-24 hours, or slow, with a half-life of 1-30 days.

[0056] In some embodiments, compositions comprising the ADS compounds described herein are provided. In some embodiments, compositions comprising the ADS compounds or combinations thereof may be pharmaceutical compositions. The compositions disclosed herein may be pharmaceutical compositions comprising an effective amount of the compounds of the pharmaceutically acceptable carrier or vehicle described herein. In some embodiments, the compositions may be injectable ophthalmic compositions.

[0057] In some embodiments of the pharmaceutical composition, the compounds disclosed herein (e.g., ADS compounds) may be present in an effective amount (e.g., a therapeutically effective amount). The effective amount may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and overall health status of the subject, the use of excipients, the possibility of concomitant use with other therapeutic measures such as the use of other agents, and the judgment of the treating physician. In some embodiments, for example, when the compositions described herein may be used to treat eye diseases in patients such as age-related macular degeneration (AMD), the treating physician may adjust the dosage and administration regimen based on the stage or type of AMD.

[0058] In some aspects, the effective amount of the ADS compound described herein (e.g., in the formulation) may be in the range of about 0.01 mg to about 10 mg per eye, for example, in intravitreal injection (e.g., about 0.01 mg to about 9 mg, about 0.01 mg to about 8.5 mg, about 0.01 mg to about 8 mg, about 0.01 mg to about 7.5 mg, about 0.01 mg to about 7 mg, about 0.01 mg to about 6.5 mg, about 0.01 mg to about 6 mg, about 0.01 mg to about 5.5 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 4.5 mg, about 0.01 mg to about 4 mg, about 0.01 mg to about 3.5 mg, about 0.01 mg to about 3 mg, about 0.01 mg to about 2.5 mg, about 0.01 mg to about 2 mg, about 0.01 mg to about 1.5 mg, about 0.01 mg) mg~1 mg, 0.01 mg~0.5 mg, 0.01 mg~0.1 mg, 0.5 mg~10 mg, 1 mg~10 mg, 1.5 mg~10 mg, 2 mg~10 mg, 2.5 mg~10 mg, 3 mg~10 mg, 3.5 mg~10 mg, 4 mg~10 mg, 4.5 mg~10 mg, 5 mg~10 mg, 5.5 mg~10 mg, 6 mg~10 mg, 6.5 mg~10 mg, 7 mg~10 mg, 7.5 mg~10 mg, 8 mg~10 mg, 8.5 mg~10 mg, 9 mg~10 mg, 9.5 mg~10 mg, 0.01 mg~1 mg, about 0.02 mg to about 1 mg, approximately 0.03 mg to approximately 1 mg, approximately 0.04 mg to approximately 1 mg, approximately 0.05 mg to approximately 1 mg, approximately 0.06 mg to approximately 1 mg, approximately 0.07 mg to approximately 1 mg, approximately 0.08 mg to approximately 1 mg, approximately 0.09 mg to approximately 1 mg, approximately 0.1 mg to approximately 1 mg, approximately 0.2 mg to approximately 1 mg, approximately 0.3 mg to approximately 1 mg, approximately 0.4 mg to approximately 1 mg, about 0.5 mg to about 1 mg, about 0.6 mg to about 1 mg, about 0.7 mg to about 1 mg, about 0.8 mg to about 1 mg, about 0.The effective doses are approximately 9 mg to 1 mg, 1 mg to 2 mg, 2 mg to 3 mg, 3 mg to 4 mg, 4 mg to 5 mg, 5 mg to 6 mg, 6 mg to 7 mg, 7 mg to 8 mg, and 8 mg to 9 mg. In some embodiments, the effective dose of the ADS compound described herein is approximately 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0059] In some embodiments, the composition may include a vehicle. The vehicle may act as a carrier or solvent for one or more ADS compounds. In some embodiments, the composition may be in the form of a solution, suspension, or emulsion. In some embodiments, the compositions provided herein may consist essentially of one or more ADS compounds, or combinations thereof. In some embodiments, the composition may be an organic composition that does not contain aqueous components.

[0060] In some respects, the vehicle can be buffered saline.

[0061] In some cases, the vehicle has a fat content of approximately 0% to 99.9% (w / w), approximately 0.1% to 99.9% (w / w), approximately 0.1% to 30% (w / w), approximately 1% to 25% (w / w), approximately 1% to 20% (w / w), approximately 5% to 20% (w / w), approximately 5% to 15% (w / w), approximately 10% to 99.9% (w / w), approximately 20% to 99.9% (w / w), approximately 30% to 99.9% (w / w), approximately 40% to 99.9% (w / w), approximately 50% to 99.9% (w / w), approximately 60% to 99.9% (w / w), approximately 65% ​​to 99.9% (w / w), and approximately 70% to 99.9%. (w / w), approximately 75% to 99.9% (w / w), approximately 80% to 99.9% (w / w), approximately 85% to 99.9% (w / w), approximately 90% to 99.9% (w / w), approximately 95% to 99.9% (w / w), approximately 98% to 99.9% (w / w), approximately 20% to 80% (w / w), approximately 20% to 70% (w / w), approximately 20% to 60% (w / w), approximately 20% to 50% (w / w), approximately 20% to 40% (w / w), approximately 20% to 30% (w / w), approximately 30% to 80% (w / w), approximately 40% to 80% (w / w), approximately 50% to 80% (w / w), approximately 60% to 80% (w / w), approximately 70% to 80% (w / w), approximately 99.9% (w / w), approximately 99% (w / w), approximately 98% (w / w), approximately 97% (w / w), approximately 96% (w / w), approximately 95% (w / w), approximately 94% (w / w), approximately 93% (w / w), approximately 92% (w / w), approximately 91% (w / w), approximately 90% (w / w), approximately 85% (w / w), approximately 80% (w / w), approximately 75% (w / w), approximately 70% (w / w), approximately 65% ​​(w / w), approximately 60% (w / w), approximately 55% (w / w), approximately 50% (w / w), approximately 45% (w / w), approximately 40% It may be present in amounts of (w / w), approximately 35% (w / w), approximately 30% (w / w), approximately 25% (w / w), approximately 20% (w / w), approximately 15% (w / w), approximately 10% (w / w), approximately 9% (w / w), approximately 8% (w / w), approximately 7% (w / w), approximately 6% (w / w), approximately 5% (w / w), approximately 4% (w / w), approximately 3% (w / w), approximately 2% (w / w), approximately 1% (w / w), approximately 0.5% (w / w), or approximately 0.1% (w / w).

[0062] In some cases, the dosage may be administered once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, once every twelve months, once every thirteen months, once every fourteen months, once every fifteen months, once every sixteen months, once every seventeen months, or once every eighteen months.

[0063] In some embodiments, the composition can remain stable or storage stable for more than 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, and 25 months.

[0064] The pharmaceutical composition may also contain one or more additional therapeutic agents, excipients, or diluents, including but not limited to absorbents, anti-irritants, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film-forming / retaining agents, formulating agents, surfactants / detergents, penetration enhancers, viscosity enhancers, and thickeners.

[0065] The pharmaceutical compositions of this application may include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration for the ADS compounds or compositions described herein include intravitreous, intrachorionic, suprachoroidal, subconjunctival, subtenon's capsule, subretinal, or topical intraocular delivery, or other methods of delivery to either the posterior or anterior part of the eye for the treatment of various ocular neovascular diseases.

[0066] In some embodiments, the release rate of the small molecule agent can be determined based on the progression of the disease. In some embodiments, the number of small molecule agents linked to each antibody in the ADS compound can be selected to achieve a specific desired release amount of antibody, small molecule agent, or both.

[0067] In some embodiments, the composition is prepared by homogeneously and closely combining the ADS compound of the Disclosure with the liquid vehicle of the Disclosure.

[0068] In some embodiments, the compositions may be in emulsion form. The disclosure also includes, for example, pharmaceutical kits useful for the treatment of disorders, diseases, and conditions referred to herein, the kits comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the disclosure. Such kits may further include, as necessary, one or more of various conventional pharmaceutical kit components, such as, additional containers, for example, containers containing one or more pharmaceutically acceptable carriers. Instructions, either in the form of inserts or labels, indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit. The kit may optionally include additional therapeutic agents as described herein. In some embodiments, the kit may include a dispensing device pre-filled with the compositions as described herein.

[0069] This specification provides methods for treating diseases or conditions in a subject using compounds, compositions, and methods described herein. In some embodiments, the disease or condition is selected from graft-versus-host disease, cancer, tumor, or nephropathy.

[0070] This specification also provides methods for treating ocular diseases or conditions using the compounds, compositions, and methods described herein. In some embodiments, the ocular disease or condition may be age-related macular degeneration (AMD). AMD may be dry AMD or exudative AMD. AMD may be early AMD, mid-stage AMD, late AMD, or late AMD with geographic atrophy (GA). In some embodiments, the disease or condition may be geographic atrophy (GA) secondary to AMD. In some embodiments of the compounds, compositions, and methods described herein, administration of the compounds or compositions may prevent or delay the progression of AMD to later stages. In some embodiments, the ocular disease or condition may be graft-versus-host disease, such as post-corneal transplantation, or ocular neoplastic diseases, such as retinal hemangioblastoma or retinal astrocytic hamartoma.

[0071] An effective amount of the ADS compounds described herein or combinations thereof, or an effective amount of a composition containing the ADS compounds described herein, can be administered to various body tissues or biological tissues. In some embodiments, exemplary body tissues or biological tissues include, but are not limited to, the mammalian ocular environment, such as the vitreous humor, a portion of the posterior segment of the eye, ocular tissue, or ocular cells. In some embodiments, the tissue may be present in or on the body of the subject. In some embodiments, the tissue may be ex vivo or in vitro.

[0072] In some embodiments, the ADS compounds or compositions described herein can be delivered to the target eye for the treatment of various ocular neovascular diseases by means of intravitreous, intrachorionic, suprachoroidal, subconjunctival, subtenon's capsule, subretinal, or topical intraocular delivery, or by other means of delivery to either the posterior or anterior part of the eye. In some embodiments, the ADS compounds or compositions described herein can be delivered to the target eye by intravitreous injection.

[0073] The compounds, compositions, and methods described herein are indicated for wet or exudative AMD or GA secondary to AMD, as well as for other neovascular and fibrotic indications, such as other types and stages of age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), epiretinal membrane (ERM), macular hole, myopia-associated choroidal neovascularization, striata, retinal detachment, diabetic retinopathy, atrophic changes in the retinal pigment epithelium (RPE), hypertrophic changes in the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, glaucoma, inflammatory conditions, uveal melanoma, corneal neovascularization, ocular surface tumors, retinopathy of prematurity, anterior ocular neovascularization, keratitis, or corneal transplantation. It may also be useful for corneal neovascularization after transplantation or keratoplasty, corneal neovascularization due to hypoxia, pterygium, or macular edema (e.g., cystoid macular edema (CME), diabetic macular edema (DME), macular edema due to retinal vein occlusion, subretinal edema, intraretinal edema, postoperative edema, or uveal edema, but not limited to these).

[0074] The present invention is further illustrated in the following examples, but these examples are not intended to limit the scope of the invention. While the invention is described in detail, it should be understood that the above description is illustrative and not intended to limit the scope of the invention as defined by the appended claims. Further aspects, advantages, and modifications are within the scope of the appended claims.

[0075] Numbered form Appearance 1. Anti-complement antibodies or manipulated biological molecules; Small molecules selected from multi-kinase inhibitors (MKIs) and anti-angiogenic inhibitors; and A linker for linking the antibody to the small molecule, which is capable of cleaving in the eye environment of a mammal. A compound containing [this compound]. Appearance 2. The compound according to embodiment 1, wherein the anti-complement antibody or manipulated biological molecule is selected from anti-C3 antibody, anti-C3b antibody, anti-factor B antibody, anti-factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and anti-factor H antibody. Appearance 3. The compound of Embodiment 1 or Embodiment 2, wherein the anti-complement antibody or manipulated biological molecule is selected from pegcetacoplan, eculizumab, ravulizumab, and abasincaptadopegol. Appearance 4. The aforementioned MKIs are canertinib, crenolanib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lenvatinib, linifanib, motesanib, neratinib, quizartinib, tandutinib, civantinib, cibozanib, batalanib, cejiranib, trametinib, dabrafenib, vemurafenib, palbociclib, amvatinib, dasatinib, foretinib, gorbachi One compound selected from nib, imatinib, nilotinib, pazopanib, crizotinib, sunitinib, sorafenib, axitinib, ponatinib, ruxolitinib, vandetanib, cabozantinib, afatinib, ibrutinib, nintedanib, regorafenib, idelalisib, ceritinib, LY2874455, and SU5402, or any combination thereof, as described in any one of embodiments 1 to 3. Appearance 5. The anti-angiogenic inhibitor is a compound selected from squalamine or a corticosteroid, one of any one of embodiments 1 to 4. Appearance 6. The aforementioned mammalian eye environment is selected from vitreous fluid, a portion of the posterior segment of the eye, or eye tissue, and is one of any one of embodiments 1 to 5. Appearance 7. A compound in any one of embodiments 1 to 6, wherein the linker is selected from those containing an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or hydrazone bond. Appearance 8. The linker The filename is TIFF2026521989000004.tif17128. In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkyl heteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl. A compound from any one of embodiments 1 to 6. Appearance 9. A compound in any one of embodiments 1 to 8, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. Appearance 10. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. Compound according to embodiment 9. Appearance 11. A compound according to any one of embodiments 9 to 10, wherein the linker links the small molecule drug to the antibody or engineered biological molecule via the PEG portion. Appearance 12. A compound according to any one of embodiments 1, 10, or 11, wherein the linker comprises a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM). Appearance 13. The compound according to embodiment 12, wherein the linker comprises an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or PEG linked to a hydrazone bond. Appearance 14. A compound according to any one of embodiments 1 to 13, wherein the antibody or manipulated biological molecule is an anti-C3 antibody or a manipulated biological molecule, or an anti-C5 antibody or a manipulated biological molecule. Appearance 15. The small molecule is selected from axitinib, cediranib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, batalanib, LY2874455, and SU5402, and is any one compound from embodiments 1 to 14. Appearance 16. The compound according to embodiment 15, wherein the small molecule is axitinib. Appearance 17. The antibody or manipulated biological molecule is pegcetacoplan, abasincaptadopegol, or abasincaptadopegol; and The aforementioned small molecule is axitinib. A compound from any one of embodiments 1 to 16. Appearance 18. Small molecule complement inhibitors; Antibodies or engineered biological molecules that are inhibitors of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and A linker for linking an antibody or manipulated biological molecule to a small molecule, which is capable of cleaving in the mammalian eye environment. A compound containing [this compound]. Appearance 19. The compound according to embodiment 18, wherein the complement inhibitor is selected from C3 inhibitors, C3b inhibitors, C5 inhibitors, C5a inhibitors, C5b inhibitors, factor B inhibitors, factor D inhibitors, factor H inhibitors, and CD46 inhibitors. Appearance 20. The compound according to embodiment 18 or 19, wherein the antibody or manipulated biological molecule is a VEGF-A antibody or a manipulated biological molecule. Appearance 21. The antibody or manipulated biological molecule is selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and convercept, and is any one compound of any one of embodiments 18 to 20. Appearance 22. The aforementioned mammalian eye environment is selected from vitreous fluid, a portion of the posterior segment of the eye, eye tissue, or eye cells, and is one of any one of the compounds in any of embodiments 18 to 21. Appearance 23. A compound from any one of embodiments 18 to 22, wherein the linker is selected from those containing an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or hydrazone bond. Appearance 24. The linker The filename is TIFF2026521989000005.tif17128. In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkyl heteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl. A compound from any one of embodiments 18 to 22. Appearance 25. A compound according to any one of embodiments 18 to 24, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. Appearance 26. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. Compound according to embodiment 25. Appearance 27. The compound according to embodiment 25 or 26, wherein the linker links the small molecule drug to the antibody or engineered biological molecule via the PEG portion. Appearance 28. The complement inhibitor is selected from C3 inhibitors, C3b inhibitors, C5 inhibitors, C5a inhibitors, and C5b inhibitors, and is one compound from any of embodiments 18 to 27. Appearance 29. The compound according to embodiment 28, wherein the complement inhibitor is abacopan, abasincaptadopegol, or pegcetacopan. Appearance 30. A compound according to any one of embodiments 18 to 29, wherein the antibody is aflibercept. Appearance 31. A first antigen-binding site that binds to a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and A second antigen-binding site that binds to at least some of the complement proteins selected from factor B, factor D, C5, C5a, CD46, and factor H. Bispecific antibodies or engineered biological molecular compounds containing such antibodies. Appearance 32. A compound according to embodiment 31, wherein the first antigen-binding site binds to at least a portion of VEGF-A. Appearance 33. A compound in any one embodiment of 31 or 32, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. Appearance 34. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. Compound according to embodiment 33. Appearance 35. A composition comprising one of the compounds described in embodiments 1 to 34. Appearance 36. A composition according to embodiment 35, which is an injectable ophthalmic preparation. Appearance 37. A method for treating a disease, comprising the step of administering one compound from any of embodiments 1 to 34 or one composition from any of embodiments 35 to 36. Appearance 38. The method according to embodiment 37, wherein the linker is hydrolyzed over time in the target so that both the antibody and the small molecule exert their functions in the target. Appearance 39. The method according to any one of embodiments 37 to 38, wherein the disease is selected from graft-versus-host disease, cancer, tumor, or nephropathy. Appearance 40. A method for treating an eye disease, comprising the step of administering one compound from any of embodiments 1 to 27 or one composition from any of embodiments 28 to 31 to the eye of a target, one of embodiments 37 to 38. Appearance 41. The method according to aspect 40, wherein the eye disease is selected from age-related macular degeneration (AMD), graft-versus-host disease, retinal hemangioblastoma, and retinal astrocytic hamartoma. Appearance 42. The method according to aspect 41, wherein the eye disease is age-related macular degeneration (AMD). Appearance 43. The method of embodiment 42, wherein AMD is a leaking AMD. Appearance 44. The method according to embodiment 42, wherein AMD is a dry-type AMD. Appearance 45. One of the embodiments 42 to 44, wherein AMD is either early AMD or mid-AMD. Appearance 46. AMD is late-model AMD, in any one of the methods described in embodiments 42 to 44. Appearance 47. The method according to embodiment 46, wherein late-stage AMD is exudative AMD, AMD with geographic atrophy (GA), or a combination thereof. Appearance 48. The method is one of the embodiments 40 to 47, wherein the eye disease is geographic atrophy (GA) secondary to AMD. Appearance 49. The method according to embodiment 48, wherein the subject experiences a decrease in the mean rate of change of the square root of the GA area after administration of the compound or composition. Appearance 50. A method according to embodiment 48, wherein the subject experiences a delay or cessation of GA growth. Appearance 51. Any one of embodiments 40 to 50, wherein the administration step includes delivery or injection into the eye of the subject via intravitreous, intrachorium, subretinal, or choroidal delivery.

[0076] Other aspects The present invention is described in conjunction with the detailed description above, but it should be understood that the above description is illustrative and not intended to limit the scope of the application as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. Anti-complement antibodies or manipulated biological molecules; Small molecules selected from multi-kinase inhibitors (MKIs) and anti-angiogenic inhibitors; and A linker for linking the antibody to the small molecule, which is capable of cleaving in the eye environment of a mammal. A compound containing [this compound].

2. The compound according to claim 1, wherein the anti-complement antibody or manipulated biological molecule is selected from anti-C3 antibody, anti-C3b antibody, anti-factor B antibody, anti-factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and anti-factor H antibody.

3. The compound according to claim 1 or claim 2, wherein the anti-complement antibody or manipulated biological molecule is selected from pegcetacoplan, eculizumab, ravulizumab, and abasincaptadopegol.

4. The aforementioned MKIs are canertinib, clenoranib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, lenvatinib, linifanib, motesanib, neratinib, quizartinib, tandutinib, civantinib, cibozanib, batalanib, cejiranib, trametinib, dabrafenib, vemurafenib, palbociclib, amvatinib, dasatinib, foretinib, golbatinib A compound according to any one of claims 1 to 3, selected from imatinib, nilotinib, pazopanib, crizotinib, sunitinib, sorafenib, axitinib, ponatinib, ruxolitinib, vandetanib, cabozantinib, afatinib, ibrutinib, nintedanib, regorafenib, idelalisib, ceritinib, LY2874455, and SU5402, or a combination thereof.

5. The compound according to any one of claims 1 to 4, wherein the anti-angiogenic inhibitor is selected from squalamine or a corticosteroid.

6. The compound according to any one of claims 1 to 5, wherein the ocular environment of the mammal is selected from vitreous fluid, a part of the posterior segment of the eye, or ocular tissue.

7. The compound according to any one of claims 1 to 6, wherein the linker is selected from those comprising an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or hydrazone bond.

8. The linker And, In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkyl heteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl. The compound according to any one of claims 1 to 6.

9. The compound according to any one of claims 1 to 8, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

10. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. The compound according to claim 9.

11. The compound according to any one of claims 9 to 10, wherein the linker links the small molecule drug to the antibody or engineered biological molecule via the PEG portion.

12. The compound according to any one of claims 1, 10, or 11, wherein the linker comprises a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM).

13. The compound according to claim 12, wherein the linker comprises an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or PEG linked to a hydrazone bond.

14. The compound according to any one of claims 1 to 13, wherein the antibody or manipulated biological molecule is an anti-C3 antibody or a manipulated biological molecule, or an anti-C5 antibody or a manipulated biological molecule.

15. The compound according to any one of claims 1 to 14, wherein the small molecule is selected from axitinib, cediranib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, batalanib, LY2874455, and SU5402.

16. The compound according to claim 15, wherein the small molecule is axitinib.

17. The antibody or manipulated biological molecule is pegcetacoplan, abasincaptadopegol, or abasincaptadopegol; and The aforementioned small molecule is axitinib. The compound according to any one of claims 1 to 16.

18. Small molecule complement inhibitors; Antibodies or engineered biological molecules that are inhibitors of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and A linker for linking an antibody or manipulated biological molecule to a small molecule, which is capable of cleaving in the mammalian eye environment. A compound containing [this compound].

19. The compound according to claim 18, wherein the complement inhibitor is selected from C3 inhibitors, C3b inhibitors, C5 inhibitors, C5a inhibitors, C5b inhibitors, factor B inhibitors, factor D inhibitors, factor H inhibitors, and CD46 inhibitors.

20. The compound according to claim 18 or 19, wherein the antibody or manipulated biological molecule is a VEGF-A antibody or a manipulated biological molecule.

21. The compound according to any one of claims 18 to 20, wherein the antibody or manipulated biological molecule is selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and convercept.

22. The compound according to any one of claims 18 to 21, wherein the ocular environment of the mammal is selected from vitreous fluid, a portion of the posterior part of the eye, ocular tissue, or ocular cells.

23. The compound according to any one of claims 18 to 22, wherein the linker is selected from those comprising an ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide, or hydrazone bond.

24. The linker And, In the formula, R is H, -C1-18 alkyl, -aryl, heteroaryl, -C1-18 alkylaryl, or -alkyl heteroaryl, preferably R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl. The compound according to any one of claims 18 to 22.

25. The compound according to any one of claims 18 to 24, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

26. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. The compound according to claim 25.

27. The compound according to claim 25 or 26, wherein the linker links the small molecule drug to the antibody or engineered biological molecule via the PEG portion.

28. The compound according to any one of claims 18 to 27, wherein the complement inhibitor is selected from a C3 inhibitor, a C3b inhibitor, a C5 inhibitor, a C5a inhibitor, and a C5b inhibitor.

29. The compound according to claim 28, wherein the complement inhibitor is avacopan, abasincaptadopegol, or pegcetacopan.

30. The compound according to any one of claims 18 to 29, wherein the antibody is aflibercept.

31. A first antigen-binding site that binds to a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and A second antigen-binding site that binds to at least some of the complement proteins selected from factor B, factor D, C5, C5a, CD46, and factor H. Bispecific antibodies or engineered biological molecular compounds containing such antibodies.

32. The compound according to claim 31, wherein the first antigen-binding site binds to at least a portion of VEGF-A.

33. The compound according to any one of claims 31 or 32, wherein the antibody or manipulated biological molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

34. The aforementioned PEG portion is -(CH2-CH2-O-)n-, n is between 5 and 30 or between 10 and 15. The compound according to claim 33.

35. A composition comprising the compound described in any one of claims 1 to 34.

36. The composition according to claim 35, which is an injectable ophthalmic preparation.

37. A method for treating a disease, comprising the step of administering a compound according to any one of claims 1 to 34 or a composition according to any one of claims 35 to 36.

38. The method according to claim 37, wherein the linker is hydrolyzed over time in the subject so that both the antibody and the small molecule exert their functions in the subject.

39. The method according to any one of claims 37 to 38, wherein the disease is selected from graft-versus-host disease, cancer, tumor, or nephropathy.

40. The method according to any one of claims 37 to 38, comprising the step of administering a compound according to any one of claims 1 to 27 or a composition according to any one of claims 28 to 31 to an eye of interest.

41. The method according to claim 40, wherein the eye disease is selected from age-related macular degeneration (AMD), graft-versus-host disease, retinal hemangioblastoma, and retinal astrocytic hamartoma.

42. The method according to claim 41, wherein the eye disease is age-related macular degeneration (AMD).

43. The method according to claim 42, wherein AMD is a leaking AMD.

44. The method according to claim 42, wherein AMD is a dry-type AMD.

45. The method according to any one of claims 42 to 44, wherein AMD is early AMD or mid-AMD.

46. The method according to any one of claims 42 to 44, wherein AMD is late-model AMD.

47. The method according to claim 46, wherein late-stage AMD is exudative AMD, AMD with geographic atrophy (GA), or a combination thereof.

48. The method according to any one of claims 40 to 47, wherein the eye disease is geographic atrophy (GA) secondary to AMD.

49. The method according to claim 48, wherein the subject experiences a decrease in the mean rate of change of the square root of the GA area after administration of the compound or composition.

50. The method according to claim 48, wherein the subject experiences a delay or cessation of GA growth.

51. The method according to any one of claims 40 to 50, wherein the administration step includes delivering or injecting into the eye of the subject via intravitreous, intrachorium, subretinal, or choroidal delivery.

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