Complement antibody-drug conjugates

Abstract

The present application provides Antibody-Drug Synergism compounds, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. The Antibody-Drug Synergism compounds can comprise an antibody, such as an anti-angiogenesis or anti-VEGF antibody connected by a linker to a small molecule complement inhibitor; or an anti-complement antibody connected by a linker to a small molecule inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR. The linker connecting the antibody and the drug is hydrolysable over time in the eye pf a subject, so that both the antibody and the drug exert their functions in the subject's eye. The compounds and compositions can confer better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound. Methods of treating age-related macular degeneration using the ADS compounds and compositions are also provided.

Description

[0001] COMPLEMENT ANTIBODY-DRUG CONJUGATES

[0002] CLAIM OF PRIORITY

[0003] This application claims priority to U.S. Provisional Application No. 63 / 469,775 filed on May 30, 2023; the entire contents of which are hereby incorporated by reference.

[0004] TECHNICAL FIELD

[0005] This disclosure relates to antibody-drug synergism compounds, compositions thereof, and methods for using the compounds.

[0006] BACKGROUND

[0007] Age-related macular degeneration (AMD) is a disease that can cause loss of central vision in people over age 50. It is one of the most common causes of severe loss of eyesight in this age group. There are two primary types of AMD. In exudative AMD, abnormal blood vessels growing behind the retina, leak or bleed under the retina, and lead to associated central vision loss. Anti-VEGF (vascular endothelial growth factor) agents have been used for ophthalmic indications, including for the treatment of exudative AMD. These agents are delivered by injection into the eye.

[0008] Dry AMD occurs more slowly, traversing early, middle, and late stages. In dry AMD, cells in the macula break down over time. There is currently no treatment for the early and middle stages of dry AMD, and until recently, no treatment for dry AMD at all. Geographic atrophy (GA) is the final stage of dry AMD, in which patients develop blind spots in their central vision and other losses of visual acuity. It is believed the complement cascade plays a role in GA, and a complement inhibitor, pegcetacoplan, delivered by injection, was recently approved as the first treatment for GA.

[0009] SUMMARY

[0010] Anti-angiogenesis strategies are effective treatments for ocular neovascular diseases such as exudative AMD (also known as wet AMD). Although anti-VEGF agents have been in use for the treatment of exudative AMD, these treatments target only one of the potential pathways that play a role in the pathogenesis of exudative AMD. Despite the effectiveness of these drugs, further improvements are needed for better treatment of exudative AMD. For example, targeting additional pathogenesis-related factors besides VEGF, longer interval i between injections, and the need to treat treatment-refractory patients are currently unmet. There is currently no single treatment that targets multiple pathways, both angiogenic and non-angiogenic, that are involved in the pathogenesis of exudative AMD. Additional medications may also be administered in addition to the anti-VEGF agents, but these require additional ocular injections for the patient. Ocular injections can be associated with increased risk of retinal detachment and infection that can lead to endophthalmitis, therefore increasing the number of injections in a patient is not ideal. Additionally, the need for frequent injections increases treatment burden and reduces patient compliance which can lead to suboptimal visual acuity results. Alternate options for treating exudative AMD are needed, including treatments that can target multiple pathways responsible for the pathogenesis of the disease.

[0011] Although new medications are available to treat end stage dry AMD with GA, it is currently the only treatment for dry AMD, and targets only single component of the complement pathway, and only the end stage of the disease. More treatment options are needed for dry AMD, including more options that can provide increased effectiveness against the disease and earlier treatment options targeting earlier stages of the disease.

[0012] It is believed the complement pathway plays an instrumental role in the pathogenesis of AMD and is involved in both end-stage outcomes of dry AMD - GA and exudative AMD. Therefore, inhibiting the complement pathway may be beneficial for preserving vision and halting the progress of the disease in both dry and exudative AMD. To date, there are no approved ophthalmic treatments that inhibit both the angiogenesis pathway or VEGF pathway and the complement pathway in a single therapeutic agent.

[0013] Furthermore, clinical trials of complement inhibitors such as pegcetacoplan have demonstrated an increased risk for exudative AMD conversion, which is believed to be a direct effect of complement inhibition. Inhibiting both complement and VEGF may help to minimize or prevent this sight-threatening side effect.

[0014] This disclosure relates to Antibody-Drug Synergism compounds, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. The Antibody -Drug Synergism compounds can comprise an antibody, such as a classic antibody or a modified or engineered biologic molecule that blocks a first target in a subject, such as a first pathogenic pathway; a drug or therapeutic agent, such as a molecular agent or small molecule agent that blocks the first target or a second target, such as a second pathogenic pathway or a second component of the first pathogenic pathway, in the subject; and a linker connecting the antibody and the drug, wherein the linker is hydrolysable over time in the subject, such as in the eye of the subject, so that both the antibody and the drug exert their functions simultaneously. In some instances the first target can be any of the angiogenesis related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF and FGFR. In some instances the second target can be a complement pathway target such as C3, C3b, C5, C5a, C5b, Factor B, Factor D, Factor H, and CD46. In some instances, the first target can be a complement pathway target such as C3, C3b, C5, C5a, C5b, Factor B, Factor D, Factor H, and CD46. In some instances the second target can be any of the angiogenesis related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF and FGFR. In some instances, the first target can be any of the angiogenesis related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF and FGFR; and the second target can be a complement pathway target such as C3, C3b, C5, C5a, C5b, Factor B, Factor D, Factor H, and CD46. In some instances, the first target can be a complement pathway target such as C3, C3b, C5, C5a, C5b, Factor B, Factor D, Factor H, and CD46; and the second target can be any of the angiogenesis related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF and FGFR. The compounds and compositions can, in some instances, confer better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound.

[0015] In another aspect, this disclosure relates also to synergistic bi-specific antibody compounds, compositions, and methods for treating ocular diseases such as dry AMD, GA secondary to AMD, and exudative AMD. The synergistic bi-specific antibody compounds can comprise a single antibody, such as a classic antibody or a modified biologic molecule that blocks a first target in a subject, such as a VEGF or angiogenic pathway; and a second target, such as a complement pathway, in the subject. Thus, in some embodiments, the bi- specific antibody can comprise an antibody that is designed to block a first target which is any 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. The compounds and compositions can, in some instances, confer better efficacy than either antibody alone due to a synergism of the bispecific antibody compound.

[0016] In one aspect, described herein is a compound comprising: an anti-complement antibody or engineered biologic molecule; a small molecule selected from a multikinase inhibitor (MKI) and an antiangiogenesis inhibitor; and a linker that links the antibody to the small molecule, wherein the linker is cleavable in a mammalian ocular environment. In this and other embodiments, the compound can optionally have the following features. The anti-complement antibody or engineered biologic molecule can be selected from an anti- C3 antibody, anti-C3b antibody, anti-Factor B antibody, anti-Factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and an anti-Factor H antibody. The anti-complement antibody or engineered biologic molecule can be selected from pegcetacoplan, eculizumab, ravulizumab, pegcetacoplan, and avacincaptad pegol. The MKI can be selected from Canertinib, Crenolanib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Lenvatinib, Linifanib, Motesanib, Neratinib, Quizartinib, Tandutinib, Tivantinib, Tivozanib, Vatalanib, Cediranib, Trametinib, Dabrafenib, Vemurafenib, Palbociclib, Amuvatinib, Dasatinib, Foretinib, Golvatinib, Imatinib, Nilotinib, Pazopanib, Crizotinib, Sunitinib, Sorafenib, Axitinib, Ponatinib, Ruxolitinib, Vandetanib, Cabozantinib, Afatinib, Ibrutinib, Nintedanib, Regorafenib, Idelalisib, Ceritinib, LY2874455, and SU5402, or a pharmaceutically acceptable salt thereof, or combinations thereof. The anti-angiogenesis inhibitor can be selected from squalamine or a corticosteroid. The mammalian ocular environment can be selected from vitreous humor, a portion of a posterior segment of an eye, or an ocular tissue. The linker can be selected from comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a urea, a sulfonamide, or a hydrazone bond.

[0017] In some aspects, the linker can optionally be: wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -Cl-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 can optionally have the following further features. The antibody or engineered biologic 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-, and n can be 5-30, or n can be 10-15. The linker can link the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule. The linker can include a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM). The linker can comprise PEG tethered to the ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide or hydrazone bond. The antibody or engineered biologic molecule can be an anti-C3 antibody or engineered biologic molecule or an anti- C5 antibody or engineered biologic molecule. The small molecule can be selected from Axitinib, Cediranib, Linifanib, Motesanib, Nintedanib, Pazopanib, Ponatinib, Regorafenib, Sorafenib, Sunitinib, Tivozanib, Vatalanib, LY2874455, and SU5402. The small molecule can be axitinib In some cases, the antibody or engineered biologic molecule can be pegcetacoplan or avacincaptad pegol; and the small molecule can be axitinib.

[0019] In another aspect, described herein is a compound comprising: a small molecule Complement inhibitor; an antibody or engineered biologic molecule, wherein the antibody or engineered biologic molecule is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a linker that links the antibody or engineered biologic molecule to the small molecule, wherein the linker is cleavable in a mammalian ocular environment.

[0020] In this and other embodiments, the compound can optionally have the following features. The Complement inhibitor can be selected from a C3 inhibitor, a C3b inhibitor, a C5 inhibitor, a C5a inhibitor, a C5b inhibitor, a Factor B inhibitor, a Factor D inhibitor, a Factor H inhibitor, and a CD46 inhibitor. The antibody or engineered biologic molecule can be a VEGF-A antibody or engineered biologic molecule. The antibody or engineered biologic molecule can be selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and conbercept. The mammalian ocular environment can be selected from vitreous humor, a portion of a posterior segment of an eye, an ocular tissue, or an ocular cell. The linker can be selected from comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a urea, a sulfonamide or a hydrazone bond.

[0021] In some aspects, the linker can optionally be: wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -Cl-18 alkylaryl, or - alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t- butyl, phenyl, or benzyl.

[0022] In these and other embodiments, the compound can optionally have the following further features. The antibody or engineered biologic 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-, and n can be 5-30, or n can be 10-15. The linker can link the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule. The Complement inhibitor can be selected from a C3 inhibitor, a C3b inhibitor, a C5 inhibitor, a C5a inhibitor, and a C5b inhibitor. The Complement inhibitor can be avacopan or pegcetacoplan. The antibody can be aflibercept.

[0023] In another aspect, described herein is a bispecific antibody or engineered biologic molecule compound comprising: a first antigen-binding site, wherein the first antigen-binding site binds a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a second antigen-binding site, wherein the second antigen-binding site binds at least a portion of a complement protein selected from Factor B, Factor D, C5, C5a, CD46, and Factor H.

[0024] In this and other embodiments, the compound can optionally have the following features. The first antigen-binding site can bind at least a portion of VEGF -A. The antibody or engineered biologic molecule can be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. The PEG moiety can be -(CH2- CH2-0-)n-, and n can be 5-30, or n can be 10-15.

[0025] In another aspect, described herein is a composition comprising any of the compounds described herein and above.

[0026] In this and other embodiments, the composition can optionally have the following features. The composition can be an injectable ocular formulation.

[0027] In another aspect, described herein is a method for treating a disease comprising administering to a subject any of the compounds or compositions described herein or above.

[0028] In these and other embodiments of the methods described herein, the methods can optionally have the following features. The linker can be hydrolyzed in the subject over time such that both the antibody and the small molecule exert their functions in the subject. The disease can be selected from graft versus host disease, a cancer, a tumor, or a nephropathy. The method can be a method for treating an ocular disease comprising administering to an eye of a subject any of the compounds or compositions described herein. The ocular disease can be selected from age-related macular degeneration (AMD), graft versus host disease, retinal hemangioblastoma, uveal melanomas, corneal neovascularization, ocular surface neoplasms, and retinal astrocytic hamartoma. The ocular disease can be age-related macular degeneration (AMD). The AMD can be exudative AMD. The AMD can be dry AMD. The AMD can be early stage AMD or intermediate stage AMD. The AMD can be late stage AMD. The late stage AMD can be exudative AMD, AMD with geographic atrophy (GA), or a combination thereof. The ocular disease can be geographic atrophy (GA) secondary to AMD. The subject can experience a reduction in the mean rate of change in square root GA area following administering the compound or composition. The subject can experience a slowing or stopping of GA growth. Administering can comprise delivering or injecting into an eye of the subject via intravitreal, intracam eral, subretinal, or suprachoroidal delivery.

[0029] In some instances described herein, the compounds, compositions, and methods provided herein can provide several advantages. First, in some instances of the compounds, compositions, and methods provided herein synergistic and enhanced efficacy in treating an ocular disease in a subject, such as AMD, including exudative and dry AMD, can be produced. In some instances, the antibody and the drug exert their functions simultaneously, and the ADS compound confers better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound.

[0030] Second, in some instances of the compounds, compositions and methods provided herein, the compounds can provide improved treatment of dry AMD with GA by reducing side effects and conversion to exudative AMD. Clinical trials of complement inhibitors for treatment of AMD with GA, such as pegcetacoplan, have demonstrated an increased risk for exudative AMD conversion. Without being bound by theory, it is believed this conversion to exudative AMD is a direct effect of the complement inhibition. It is further believed inhibiting both complement and VEGF will minimize or prevent this sight-threatening side effect. Thus, providing such dual-inhibition in a single treatment can provide a treatment for AMD with GA that prevents or reduces the potential side effect of conversion to exudative AMD.

[0031] Third, in some instances, the compounds, compositions and methods provided herein, can provide a single therapeutic agent that targets multiple pathways involved in the pathogenesis of AMD. Not only does such single therapeutic agent have the potential to improve outcomes by targeting more than one pathway, but a single agent approach also provides a clear advantage over injecting two agents separately into the eye which would increase the risk of infection and add to patient burden.

[0032] Fourth, in some instances, the linked compounds can provide prolonged activity of the treatment after injection. In some instances, the cleavage of the linkers will occur slowly over time, releasing the therapeutic agents and allowing for a longer duration of the treatment by slow cleavage of the agents from each other. This can prove beneficial by increasing the time between injections, which can decrease risk of infection from injections and reduce patient burden.

[0033] Fifth, in some instances, the compounds, compositions, and methods described herein can avoid potential side effects of small molecule inhibitors, such as multikinase inhibitors or complement inhibitors by ensuring local delivery based on inactivity when the ADS compound is intact and delivering activity only upon cleavage of the linker in the desired locations or tissues.

[0034] Sixth, the antibody portion of the ADS compound can act as both a carrier of the small molecule and as a therapeutic in its own activity. The carrier activity of the antibody portion can further provide the benefit of solving the difficulty of formulating a small molecule for posterior ocular delivery, such as intravitreal delivery.

[0035] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0036] DETAILED DESCRIPTION

[0037] Provided herein are antibody-drug synergism compounds, compositions, and methods for using the compounds or compositions.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0039] As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. In some embodiments, a human subject may be of any age, for example, from 0 to 100 years old.

[0040] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0041] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., reversing the pathology and / or symptomatology).

[0042] Antibody-Drug Synergism (ADS) technology is a concept that utilizes the synergy between an antibody and a small molecule agent to treat a variety of diseases, for example, an ocular disease. In this technology, an ADS compound is formed by linking a small molecule agent to an antibody drug through a linker via a covalent bond or other similar bonds. It differentiates from the oncology-focused antibody-drug conjugate (ADC) technology in three important ways: 1) The antibody in the ADS technology is used as a disease-modifying drug while the antibody in the ADC technology is merely a carrier to target the small molecule agent to cancer cells; Therefore, in ADS, antibody and small molecule have synergistic effect on the target disease while in ADC, antibody and small molecule will have no synergistic effect. 2) The linker in the disclosed method is cleaved outside of cells (for example, in vitreous humor of the eye) to release the small molecule agent while the linker in the ADC technology is cleaved inside cancer cells or not cleaved at all. 3) ADS technology also serves as a carrier to slowly break the linker to release the small molecule agent at the injection site to have prolong effect of the small molecule agent while in ADC, antibody does not serve this function. While the application focuses on ocular diseases to demonstrate the concept, the disclosed methods can be used for any diseases where local drug administration is a suitable treatment.

[0043] Ocular neovascular diseases are diseases of the eye that involve abnormal angiogenesis (blood vessel growth) and vessel leakage. Examples are exudative (wet) age- related macular degeneration (AMD), diabetic macular edema, retinal vein occlusion, diabetic retinopathy, cornea neovascularization and pterygium.

[0044] Anti-angiogenesis biologic drugs can be effective treatments for ocular neovascular diseases such as exudative AMD. Successful examples include bevacizumab (off-label use), ranibizumab, aflibercept, brolucizumab, and conbercept; all of these are VEGF-A- neutralizing biologic agents (Rosenfeld et al 2006, Martin et al 2011, Stewart et al 2012). Despite the success of these biologic drugs, there are still unmet needs for better treatment of exudative AMD. Anti-VEGF-A alone is insufficient to achieve neovascular regression, a desirable outcome for exudative AMD. Another need is to treat patients that become refractive to deprivation of VEGF-A (Jo et al 2006). To address these unmet needs, new strategies have been tested in the clinic. For example, multi-target small molecule agents have been tested as topical formulations (Csaky et al 2015). But delivering small molecule to retina via topical route proved difficult and intravitreal formulations are also fraught with problems. In addition, other signalling pathways such as the complement pathway are involved in AMD pathogenesis. These may play a role in early, mid, or late stages of disease, or severity of disease. The compounds and methods disclosed herein use a novel way to target multiple pathogenic factors such as aforementioned VEGF or anti-angiogenesis and complement signaling pathways simultaneously.

[0045] The ADS technology can be used as a novel way to treat ocular neovascular diseases, such as exudative AMD, dry AMD, or GA secondary to AMD. It utilizes the synergism between an antibody and a small molecule agent to achieve better effects than either single component alone. A technology called antibody-drug conjugate (ADC) has been used in cancer therapy. That technology links a cancer drug, usually cytotoxic agents, to an antibody that directs the drug to cancer cells and confers some selectivity. Antibody used in the ADC platform merely acts as a carrier to bind to the targeted cancer cell and does not possess therapeutic effects The ADC approach is used to improve the safety or pharmacokinetics profiles of cancer drugs (Kim et al 2015, Peters et al 2015) and the linkers in the ADC are designed to be cleaved inside cells to release the cancer drug or not to be cleaved at all. The method of the ADS platform differs from the ADC technology in three important ways. Instead of being an inactive carrier as in the ADC technology, the antibody in the ADS method is itself a therapeutic agent designed to have synergistic therapeutic effect with the small molecule agent linked to it; secondly, the linker in the disclosure is designed to be hydrolyzed in vitreous humor or other ocular tissues instead of inside cancer cells; thirdly, ADS technology also serves as a carrier to slowly break the linker to release the small molecule agent at the injection site to have prolong effect of the small molecule agent while in ADC, antibody does not serve this function. In addition to these three differences, the disclosed method is designed for ocular or other locally injected use instead of systemic cancer treatment. The ADS technology can allow modulation of multiple ocular targets to achieve synergistic therapeutic effects; in addition to being a therapeutic agent, the antibody in the disclosed method can also act as a carrier to facilitate sustained delivery of the small molecule agent to the vitreous, a task previously difficult to achieve.

[0046] The antibody in the compounds, compositions, and methods herein can be a classic antibody, an antibody hybrid fusion or any other biologic molecules or engineered biologic molecules that are 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 molecule in the compounds, compositions, and methods herein can be a multikinase inhibitor or angiogenesis inhibitor, or a complement inhibitor. In some embodiments, provided herein are ADS compounds comprising an anticomplement antibody or engineered biologic molecule; a small molecule such as a multikinase inhibitor (MKI) or an anti-angiogenesis inhibitor, and a linker that links the antibody to the small molecule, wherein the linker is cleavable in a mammalian ocular environment. Once in the ocular environment of a subject, such as, for example, in the vitreous humor, the linker can hydrolyze over time in the subject, so that both the antibody and the drug exert their functions simultaneously. These compounds can, in some instances, confer better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound.

[0047] In some embodiments, the antibody or engineered biologic molecule is an anticomplement antibody or engineered biologic molecule. The antibody in some embodiments of the compounds, compositions, and methods can be a classic antibody, an antibody hybrid fusion or any other biologic molecules that are designed to block any of the complement related targets. Non-limiting examples of the complement pathway targets for the ADS compounds described herein include C3, C3b, C5, C5a, C5b, Factor B, Factor D, Factor H, and CD46. A nonlimiting example of an anti-C3 antibody useful in the compounds and methods described herein includes pegcetacoplan. Non-limiting examples of anti-C5 antibodies or engineered biomolecules useful in the compounds and methods described herein include eculizumab, ravulizumab, and avacincaptad pegol. Non-limiting examples of anti-C5a antibodies or engineered biologic molecules include crovalimab, zilucoplan, pozelimab. In some instances described herein, the antibody can be an antibody mimetic or chemical antibody, such as an RNA aptamer. Non-limiting exemplary antibody mimetics or chemical antibodies useful as the antibody component of the ADS compound in some embodiments described herein can include avacincaptad pegol. In some embodiments, the antibody component can be an engineered biologic molecule such as pegcetacoplan. In some embodiments, the antibody can be PEGylated.

[0048] In some embodiments, the small molecule agent can be a multikinase inhibitor against one or more tyrosine kinases. Examples of the tyrosine kinase inhibitors include: Canertinib, Crenolanib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Lenvatinib, Linifanib, Motesanib, Neratinib, Quizartinib, Tandutinib, Tivantinib, Tivozanib, Vatalanib, Cediranib, Trametinib, Dabrafenib, Vemurafenib, Palbociclib, Amuvatinib, Dasatinib, Foretinib, Golvatinib, Imatinib, Nilotinib, Pazopanib, Crizotinib, Sunitinib, Sorafenib, Axitinib, Ponatinib, Ruxolitinib, Vandetanib, Cabozantinib, Afatinib, Ibrutinib, Nintedanib, Regorafenib, Idelalisib, Ceritinib, LY2874455, SU5402, and any others that inhibit VEGFR, PDGFR, and FGFR, or combinations thereof. In some embodiments, the small molecule agent can other type of anti-angiogenesis inhibitor, such as squalamine or a corticosteroid.

[0049] In some embodiments, provided herein are ADS compounds 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 the small molecule, wherein the linker is cleavable in a mammalian ocular environment. Once in the ocular environment of a subject, such as, for example, in the vitreous humor, the linker can hydrolyze over time in the subject, so that both the antibody and the drug exert their functions simultaneously. These compounds can, in some instances, confer better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound.

[0050] 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 herein can be a classic antibody, an antibody hybrid fusion or any other biologic molecules that are designed to block any of the VEGF, VEGFR, PDGF, PDGFR, FGF, FGFR, or other anti-angiogenesis related targets. Non-limiting examples of biologic drugs designed to block angiogenesis related targets include: bevacizumab and ranibizumab, ramucirumab, aflibercept, brolucizumab, and conbercept.

[0051] In addition, any anti-angiogenesis protein drugs (for example, in clinical testing but not yet approved by FDA, or newly discovered) can also be included. Non-limiting examples include anti-VEGF, -PDGF Darpins (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, Ophthotech) and any others that inhibit VEGF, PDGF, VEGFR or PDGFR. In some instances, the antibody in the disclosed methods can be mono-target or bi-target (e.g. bispecific) or multi-target biologies. In some embodiments, the compounds described herein can be used to treat non-ocular diseases. In some embodiments, the antibody or engineered biologic molecule can be a BAFF inhibitor, an anti-CD20 antibody, a RANKL inhibitor, an IL-12 antagonist, and IL-23 antagonist, an IL-1 antagonist, an IL-1 beta antagonist, a TNF inhibitor, a TNF alpha inhibitor, a complement inhibitor, a complement C5 inhibitor, an IL-6 receptor inhibitor, an inhibitor of cell adhesion molecule a4-integrin, a T cell modulator, a CD1 la binding agent or blocker, an anti-IgE antibody, a competitive antagonist of IL-2, glycoprotein Ilb / IIIa receptor antagonist, or combinations thereof. In some embodiments, the antibody or engineered biologic molecule can be selected from bevacizumab, ranibizumab, brolucizumab, aflibercept, conbercept, abeiximab, adalimumab, basiliximab, belimumab, canakinumab, certolizumab or certolizumab pegol, denosumab, eculizumab, efalizumab, golimumab, infliximab, natalizumab, omalizumab, tocilizumab, ustekinumab, or combinations thereof.

[0052] In addition, in some instances, the antibody in the disclosed methods can be PEGylated. In some embodiments, the antibody can be pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched. In some embodiments, the PEG moiety can be -(CH2-CH2-O-)n-, wherein n is 5-30 or n is 10-15. In some embodiments, the linker can link the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule.

[0053] In some instances, the compounds can comprise a small molecule complement inhibitor. Non-limiting examples of the complement pathway targets for the small molecule complement inhibitor 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 small molecule complement pathway inhibitors is avacopan. In some embodiments, the small molecule complement pathway inhibitor can be pegcetacoplan. In some embodiments, the small molecule complement pathway inhibitor can be avacincaptad pegol.

[0054] In some embodiments, such as wherein the small molecule component is an angiogenesis inhibitor, and the antibody component is an anti-complement antibody or engineered biologic molecule, pegcetacoplan can act as the antibody component. In other embodiments, such as wherein the antibody component is an anti-angiogenesis antibody or engineered biologic molecule and the small molecule component is a complement inhibitor, pegcetacoplan can act as the small molecule component.

[0055] In some embodiments, such as wherein the small molecule component is an angiogenesis inhibitor, and the antibody component is an anti-complement antibody or engineered biologic molecule, avacincaptad pegol can act as the antibody component. In other embodiments, such as wherein the antibody component is an anti-angiogenesis antibody or engineered biologic molecule and the small molecule component is a complement inhibitor, avacincaptad pegol can act as the small molecule component.

[0056] In some embodiments of the compounds, compositions, and methods described herein, the linker can be any kind of linker that can be cleaved in a mammalian ocular environments, for example in vitreous humor, a portion of a posterior segment of an eye, aqueous humor, sub-tenon, cornea, conjunctiva, choroid, ocular tissues, ocular cells, or combinations thereof. As disclosed herein, the posterior segment of the eye can include all back-of-eye tissues up to the outer retina. Examples of ocular-hydrolyzable (and in other tissues) linkers are esters, amides, carbamates, carbonates, imines, ethers, phosphates, ureas, a sulfonamide or a hydrazone bond. In some embodiments, the linker is an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a hydrazone, an acetal, or a hydrozone bond.

[0057] In some embodiments, the linker is: wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -C 1 - 18 alkylaryl, or -alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0058] Linkers used in the previous ADC platform are also included if they can be hydrolyzed in the said ocular environment. These include hydrazone, disulfide, dipeptide, beta-glucuronide (Kim and Kim 2015, Peters and Brown 2015). In some embodiments, the linkers may be selected to cleave in other target tissues, such as joint tissue, muscular tissue, blood, skin, epithelial tissue, connective tissue, nervous tissue, and the like. In addition, the linker can be a small molecule polymer conjugate. In some embodiments, the linker can include a PEG tethered to a small molecule complex. As nonlimiting example, the linker can comprise PEG tethered to the ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide or hydrazone bond. In some embodiments, the linker can include a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM)

[0059] The rate of hydrolysis of the linker can be designed to be fast with the hydrolysis halflife between 1-60 minutes, or 1-24 hours. It can also be designed to be slow with half- life between 1-30 days.

[0060] In some embodiments, provided herein are compositions comprising an ADS compound described herein. In some embodiments, compositions comprising the ADS compounds or combinations thereof can be pharmaceutical compositions. The compositions disclosed herein can be pharmaceutical compositions comprising an effective amount of a compound of pharmaceutically acceptable carrier or vehicle as described herein. In some embodiments, the compositions can be injectable ocular compositions.

[0061] In some embodiments of the pharmaceutical compositions a compound disclosed herein (e.g., an ADS compound) can be present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, in some embodiments, where the compositions described herein may be used to treat a disease in an eye of the patient, such as age-related macular degeneration (AMD), the treating physician may adjust the dosage and dosage regimen based on the stage or type of the AMD.

[0062] In some embodiments, an effective amount (e.g., in the formulation) of the ADS compounds described herein can range, for example, from about 0.01 mg per eye to about 10 mg per eye for example in intravitreal injection (e.g., per eye, from about 0.01 mg to about 9 mg, from about 0.01 mg to about 8.5 mg, from about 0.01 mg to about 8 mg, from about 0.01 mg to about 7.5 mg, from about 0.01 mg to about 7 mg, from about 0.01 mg to about 6.5 mg, from about 0.01 mg to about 6 mg, from about 0.01 mg to about 5.5 mg, from about 0.01 mg to about 5 mg, from about 0.01 mg to about 4.5 mg, from about 0.01 mg to about 4 mg, from about 0.01 mg to about 3.5 mg, from about 0.01 mg to about 3 mg, from about 0.01 mg to about 2.5 mg, from about 0.01 mg to about 2 mg; from about 0.01 mg to about 1.5 mg; from about 0.01 mg to about 1 mg; from about 0.01 mg to about 0.5 mg; from about 0.01 mg to about 0.1 mg; from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 1.5 mg to about 10 mg, from about 2 mg to about 10 mg, from about 2.5 mg to about 10 mg, from about 3 mg to about 10 mg, from about 3.5 mg to about 10 mg, from about 4 mg to about 10 mg, from about 4.5 mg to about 10 mg, from about 5 mg to about 10 mg, from about 5.5 mg to about 10 mg, from about 6 mg to about 10 mg, from about 6.5 mg to about 10 mg, from about 7 mg to about 10 mg, from about 7.5 mg to about 10 mg, from about 8 mg to about 10 mg, from about 8.5 mg to about 10 mg, from about 9 mg to about 10 mg, from about 9.5 mg to about 10 mg, from about 0.01 mg to about 1 mg, from about 0.02 mg to about 1 mg, from about 0.03 mg to about 1 mg, from about 0.04 mg to about 1 mg, from about 0.05 mg to about 1 mg, from about 0.06 mg to about 1 mg, from about 0.07 mg to about 1 mg, from about 0.08 mg to about 1 mg, from about 0.09 mg to about 1 mg, from about 0.1 mg to about 1 mg, from about 0.2 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.4 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 0.6 mg to about 1 mg, from about 0.7 mg to about 1 mg, from about 0.8 mg to about 1 mg, from about 0.9 mg to about 1 mg, from about 1 mg to about 2 mg, from about 2 mg to about 3 mg, from about 3 mg to about 4 mg, from about 4 mg to about 5 mg, from about 5 mg to about 6 mg, from about 6 mg to about 7 mg, from about 7 mg to about 8 mg, from about 8 mg to about 9 mg). In some embodiments, an effective amount of an ADS compound described herein is about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0063] In some embodiments, the compositions can comprise a vehicle. The vehicle can act as a carrier or a solvent for one or more of the ADS compounds. In some embodiments, the composition can be in the form of a solution, a suspension, or an emulsion. In some embodiments, a composition provided herein can consist essentially of one or more ADS compounds or combinations thereof. In some embodiments, the composition can be an organic composition without aqueous components.

[0064] In some embodiments, the vehicle can be buffered saline.

[0065] In some embodiments, the vehicle can be present in an amount of from about 0% to about 99.9% (w / w), from about 0.1% to about 99.9% (w / w), from about 0.1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 30% to about 99.9% (w / w), from about 40% to about 99.9% (w / w), from about 50% to about 99.9% (w / w), from about 60% to about 99.9% (w / w), from about 65% to about 99.9% (w / w), from about 70% to about 99.9% (w / w), from about 75% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w), from about

[0066] 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), from about 98% to about 99.9% (w / w), from about 20% to about 80% (w / w), from about 20% to about 70% (w / w), from about 20% to about 60% (w / w), from about 20% to about 50% (w / w), from about 20% to about 40 % (w / w), from about 20% to about 30% (w / w), from about 30% to about 80% (w / w), from about 40% to about 80% (w / w), from about 50% to about 80% (w / w), from about 60% to about 80% (w / w), from about 70% to about 80% (w / w), about 99.9% (w / w), about 99% (w / w), about 98% (w / w), about 97% (w / w), about 96% (w / w), about 95% (w / w), about 94% (w / w), about 93% (w / w), about 92% (w / w), about 91% (w / w), about 90% (w / w), about 85% (w / w), about 80% (w / w), about 75% (w / w), about 70% (w / w), about 65% (w / w), about 60% (w / w), about 55% (w / w), about 50% (w / w), about 45% (w / w), about 40% (w / w), about 35% (w / w), about 30% (w / w), about 25% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), about 1% (w / w), about 0.5% (w / w), or about 0.1% (w / w).

[0067] In some embodiments, the dosages can 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.

[0068] In some embodiments, the compositions can remain stable or shelf stable for more than six months, more than seven months, more than eight months, more than nine months, more than ten months, more than eleven months, more than twelve months, more than thirteen months, more than fourteen months, more than fifteen months, more than sixteen months, more than seventeen months, more than eighteen months, more than nineteen months, more than twenty months, more than twenty-one months, more than twenty -two months, more than twenty -three months, more than twenty -four months, more than twenty- five months.

[0069] The pharmaceutical compositions may also comprise one or more additional therapeutic agents, excipients, or diluents including, but not limited to, absorbents, antiirritants, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, prescription drugs, surfactants / detergent cleansing agents, penetration enhancers, viscosity enhancers, and thickeners.

[0070] The pharmaceutical compositions of the present application can include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration of the ADS compounds or compositions described herein include intravitreal, intracameral, suprachoroidal, subconjunctival, subtenon, subretinal, or topical ocular delivery, and the like, or other ways to deliver to either the back or front of the eye for treating various ocular neovascular diseases.

[0071] In some embodiments, the release rate of the small molecule agent can be determined based on the course of disease progression. In some embodiments, the number of small molecule agents tether to each antibody in the ADS compound can be chosen to effect a particular desired release amount for the antibody, the small molecule agent, or both.

[0072] In some embodiments, the compositions are prepared by uniformly and intimately bringing into association the ADS compounds as disclosed herein with the liquid vehicles disclosed herein.

[0073] In some embodiments, the compositions can be in an emulsion form. This disclosure also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein. In some embodiments, a kit can comprise a dispensing device preloaded with a composition as described herein.

[0074] Provided herein are methods for treating diseases or conditions in a subject using the compounds, compositions, and methods described herein. In some embodiments, the disease or conditions is selected from graft versus host disease, a cancer, a tumor, or a nephropathy.

[0075] Also provided herein are methods for treating ocular diseases or conditions using the compounds, compositions, and methods described herein. In some embodiments, the ocular diseases or condition can be age-related macular degeneration (AMD). The AMD can be dry AMD or exudative AMD. The AMD can be early stage AMD, intermediate stage AMD, late stage AMD, late stage AMD with geographic atrophy (GA). In some embodiments, the disease or condition can be geographic atrophy (GA) secondary to AMD. In some embodiments of the compounds, compositions, and methods herein, administration of the compounds or compositions can prevent or slow advancement of AMD to later stages. In some embodiments, the ocular disease or condition can be Graft versus Host disease, such as following corneal transplant, or an ocular oncological disease, such as retinal hemangioblastoma or retinal astrocytic hamartoma.

[0076] Effective amounts of an ADS compound described herein or combinations thereof, or an effective amount of a composition comprising an ADS compound described herein can be administered to various bodily tissues or biological tissues. In some embodiments, exemplary bodily tissues or biological tissues can include, without limitation, a mammalian ocular environment such as vitreous humor, a portion of a posterior segment of an eye, an ocular tissue, or an ocular cell. In some embodiments, the tissues can be in or on the body of a subject. In some embodiments, the tissues can be ex vivo or in vitro. In some embodiments, the ADS compounds or compositions described herein can be delivered to the eye of the subject via intravitreal, intracam eral, suprachoroidal, subconjunctival, subtenon, subretinal, or topical ocular delivery, and the like, or other ways to deliver to either the back or front of the eye for treating various ocular neovascular diseases. In some embodiments, the ADS compounds or compositions described herein can be delivered to the eye of the subject via intravitreal injection.

[0077] In addition to indications and diseases of wet or exudative AMD or GA secondary to AMD, the compounds, compositions, and methods herein can also be useful for other angiogenesis and fibrosis indications, for example: other types and stages of age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), epi-retinal membrane (ERM), macular hole, myopia- associated choroidal neovascularisation, vascular streaks, retinal detachment, diabetic retinopathy, atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, glaucoma, inflammatory conditions, uveal melanomas, corneal neovascularization, ocular surface neoplasms, retinopathy of prematurity, angiogenesis in the front of the eye, corneal angiogenesis following keratitis, corneal transplanation or keratoplasty, corneal angiogenesis due to hypoxia, pterygium, or macular edema, such as but not limited to cystoid macular edema (CME), diabetic macular edema (DME), macular edema due to retinal vein occlusion, subretinal edema, intraretinal edema, post-surgical edema, or uveitic edema.

[0078] The invention will be further described in the following examples, which do not limit the scope of the invention. It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0079] NUMBERED EMBODIMENTS

[0080] Embodiment 1. A compound comprising: an anti-complement antibody or engineered biologic molecule; a small molecule selected from a multikinase inhibitor (MKI) and an antiangiogenesis inhibitor; and a linker that links the antibody to the small molecule, wherein the linker is cleavable in a mammalian ocular environment.

[0081] Embodiment 2. The compound of embodiment 1, wherein the anti -complement antibody or engineered biologic molecule is selected from an anti-C3 antibody, anti-C3b antibody, anti-Factor B antibody, anti-Factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and an anti-Factor H antibody.

[0082] Embodiment 3. The compound of any one of embodiment 1 or embodiment 2, wherein the anti-complement antibody or engineered biologic molecule is selected from pegcetacoplan, eculizumab, ravulizumab, and avacincaptad pegol.

[0083] Embodiment 4. The compound of any one of embodiments 1 to 3, wherein the MKI is selected from Canertinib, Crenolanib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Lenvatinib, Linifanib, Motesanib, Neratinib, Quizartinib, Tandutinib, Tivantinib, Tivozanib, Vatalanib, Cediranib, Trametinib, Dabrafenib, Vemurafenib, Palbociclib, Amuvatinib, Dasatinib, Foretinib, Golvatinib, Imatinib, Nilotinib, Pazopanib, Crizotinib, Sunitinib, Sorafenib, Axitinib, Ponatinib, Ruxolitinib, Vandetanib, Cabozantinib, Afatinib, Ibrutinib, Nintedanib, Regorafenib, Idelalisib, Ceritinib, LY2874455, and SU5402, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0084] Embodiment 5. The compound of any one of embodiments 1 to 4, wherein the antiangiogenesis inhibitor is selected from squalamine or a corticosteroid.

[0085] Embodiment 6. The compound of any one of embodiments 1 to 5, wherein the mammalian ocular environment is selected from vitreous humor, a portion of a posterior segment of an eye, or an ocular tissue.

[0086] Embodiment 7. The compound of any one of embodiment 1 to 6, wherein the linker is selected from comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a urea, a sulfonamide, or a hydrazone bond.

[0087] Embodiment 8. The compound of any one of embodiments 1 to 6, wherein the linker is: wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -Cl-18 alkylaryl, or -alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0088] Embodiment 9. The compound of any one of embodiments 1 to 8, wherein the antibody or engineered biologic molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

[0089] Embodiment 10. The compound of embodiment 9, wherein the PEG moiety is -(CH2- CH2-O-)n-, and n is 5-30, or n is 10-15.

[0090] Embodiment 11. The compound of any one of embodiments 9 to 10, wherein the linker links the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule.

[0091] Embodiment 12. The compound of any one of embodiments 1 10 11, wherein the linker includes a small molecule polymer conjugate selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and polyacrylamide (PAM).

[0092] Embodiment 13. The compound of embodiment 12, wherein the linker comprises PEG tethered to the ester, amide, carbamate, carbonate, imine, ether, phosphate, urea, sulfonamide or hydrazone bond.

[0093] Embodiment 14. The compound of any one of embodiments 1 to 13, wherein the antibody or engineered biologic molecule is an anti-C3 antibody or engineered biologic molecule or an anti-C5 antibody or engineered biologic molecule.

[0094] Embodiment 15. The compound of any one of embodiments 1 to 14, wherein the small molecule is selected from Axitinib, Cediranib, Linifanib, Motesanib, Nintedanib, Pazopanib, Ponatinib, Regorafenib, Sorafenib, Sunitinib, Tivozanib, Vatalanib, LY2874455, and SU5402.

[0095] Embodiment 16. The compound of embodiment 15, wherein the small molecule is axitinib.

[0096] Embodiment 17. The compound of any one of embodiments 1 to 16, wherein: the antibody or engineered biologic molecule is pegcetacoplan, avacincaptad pegol, or avacincaptad pegol; and the small molecule is axitinib.

[0097] Embodiment 18. A compound comprising: a small molecule Complement inhibitor; an antibody or engineered biologic molecule, wherein the antibody or engineered biologic molecule is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a linker that links the antibody or engineered biologic molecule to the small molecule, wherein the linker is cleavable in a mammalian ocular environment.

[0098] Embodiment 19. The compound of embodiment 18, wherein the Complement inhibitor is selected from a C3 inhibitor, a C3b inhibitor, a C5 inhibitor, a C5a inhibitor, a C5b inhibitor, a Factor B inhibitor, a Factor D inhibitor, a Factor H inhibitor, and a CD46 inhibitor.

[0099] Embodiment 20. The compound of any one of embodiments 18 or 19, wherein the antibody or engineered biologic molecule is a VEGF-A antibody or engineered biologic molecule.

[0100] Embodiment 21. The compound of any one of embodiments 18 to 20, wherein the antibody or engineered biologic molecule is selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and conbercept.

[0101] Embodiment 22. The compound of any one of embodiments 18 to 21, wherein the mammalian ocular environment is selected from vitreous humor, a portion of a posterior segment of an eye, an ocular tissue, or an ocular cell.

[0102] Embodiment 23. The compound of any one of embodiments 18 to 22, wherein the linker is selected from comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a urea, a sulfonamide or a hydrazone bond.

[0103] 24. The compound of any one of embodiments 18 to 22 wherein the linker is: wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -Cl-18 alkylaryl, or -alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

[0104] Embodiment 25. The compound of any one of embodiments 18 to 24, wherein the antibody or engineered biologic molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

[0105] Embodiment 26. The compound of embodiment 25, wherein the PEG moiety is - (CH2-CH2-O-)n-, and n is 5-30, or n is 10-15.

[0106] Embodiment 27. The compound of any one of embodiments 25 or 26, wherein the linker links the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule.

[0107] Embodiment 28. The compound of any one of embodiments 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.

[0108] Embodiment 29. The compound of embodiment 28, wherein the Complement inhibitor is avacopan, avacincaptad pegol, or pegcetacoplan. Embodiment 30. The compound of any one of embodiments 18 to 29, wherein the antibody is aflibercept.

[0109] Embodiment 31. A bispecific antibody or engineered biologic molecule compound comprising: a first antigen-binding site, wherein the first antigen-binding site binds a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a second antigen-binding site, wherein the second antigen-binding site binds at least a portion of a complement protein selected from Factor B, Factor D, C5, C5a, CD46, and Factor H.

[0110] Embodiment 32. The compound of embodiment 31, wherein the first antigen-binding site binds at least a portion of VEGF-A.

[0111] Embodiment 33. The compound of any one of embodiments 31 or 32, wherein the antibody or engineered biologic molecule is pegylated to include a polyethylene glycol (PEG) moiety that is either linear or branched.

[0112] Embodiment 34. The compound of embodiment 33, wherein the PEG moiety is - (CH2-CH2-O-)n-, and n is 5-30, or n is 10-15.

[0113] Embodiment 35. A composition comprising the compound of any one of embodiments 1 to 34.

[0114] Embodiment 36. The composition of embodiment 35, wherein the composition is an injectable ocular formulation.

[0115] Embodiment 37. A method for treating a disease comprising administering to a subject the compound of any one of embodiments 1-34 or the composition of any one of embodiments 35-36.

[0116] Embodiment 38. The method of embodiment 37, wherein the linker is hydrolyzed in the subject over time such that both the antibody and the small molecule exert their functions in the subj ect.

[0117] Embodiment 39. The method of any one of embodiments 37 to 38, wherein the disease is selected from graft versus host disease, a cancer, a tumor, or a nephropathy.

[0118] Embodiment 40. The method of any one of embodiments 37 to 38 wherein the method is a method for treating an ocular disease comprising administering to an eye of a subject the compound of any one of embodiments 1-27 or the composition of any one of embodiments 28-31.

[0119] Embodiment 41. The method of embodiment 40, wherein the ocular disease is selected from age-related macular degeneration (AMD), graft versus host disease, retinal hemangioblastoma, and retinal astrocytic hamartoma.

[0120] Embodiment 42. The method of embodiment 41, wherein the ocular disease is age- related macular degeneration (AMD).

[0121] Embodiment 43. The method of embodiment 42, wherein the AMD is exudative AMD

[0122] Embodiment 44. The method of embodiment 42, wherein the AMD is dry AMD.

[0123] Embodiment 45. The method of any one of embodiments 42 to 44, wherein the AMD is early stage AMD or intermediate stage AMD.

[0124] Embodiment 46. The method of any one of embodiments 42 to 44, wherein the AMD is late stage AMD.

[0125] Embodiment 47. The method of embodiment 46, wherein the late stage AMD is exudative AMD, AMD with geographic atrophy (GA), or a combination thereof.

[0126] Embodiment 48. The method of any one of embodiments 40 to 47, wherein the ocular disease is geographic atrophy (GA) secondary to AMD.

[0127] Embodiment 49. The method of embodiment 48, wherein the subject experiences a reduction in the mean rate of change in square root GA area following administering the compound or composition.

[0128] Embodiment 50. The method of embodiment 48, wherein the subject experiences a slowing or stopping of GA growth.

[0129] Embodiment 51. The method of any one of embodiments 40 to 50, wherein administering comprises delivering or injecting into an eye of the subject via intravitreal, intracameral, subretinal, or suprachoroidal delivery.

[0130] OTHER EMBODIMENTS

[0131] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound comprising: an anti-complement antibody or engineered biologic molecule; a small molecule selected from a multikinase inhibitor (MKI) and an antiangiogenesis inhibitor; and a linker that links the antibody to the small molecule, wherein the linker is cleavable in a mammalian ocular environment.

2. The compound of claim 1, wherein the anti-complement antibody or engineered biologic molecule is selected from an anti-C3 antibody, anti-C3b antibody, anti-Factor B antibody, anti-Factor D antibody, anti-C5 antibody, anti-C5a antibody, anti-CD46 antibody, and an anti-Factor H antibody.

3. The compound of any one of claim 1 or claim 2, wherein the anti-complement antibody or engineered biologic molecule is selected from pegcetacoplan, eculizumab, ravulizumab, and avacincaptad pegol.

4. The compound of any one of claims 1 to 3, wherein the MKI is selected from Canertinib, Crenolanib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Lenvatinib, Linifanib, Motesanib, Neratinib, Quizartinib, Tandutinib, Tivantinib, Tivozanib, Vatalanib, Cediranib, Trametinib, Dabrafenib, Vemurafenib, Palbociclib, Amuvatinib, Dasatinib, Foretinib, Golvatinib, Imatinib, Nilotinib, Pazopanib, Crizotinib, Sunitinib, Sorafenib, Axitinib, Ponatinib, Ruxolitinib, Vandetanib, Cabozantinib, Afatinib, Ibrutinib, Nintedanib, Regorafenib, Idelalisib, Ceritinib, LY2874455, and SU5402, or combinations thereof.

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

6. The compound of any one of claims 1 to 5, wherein the mammalian ocular environment is selected from vitreous humor, a portion of a posterior segment of an eye, or an ocular tissue.

7. The compound of any one of claim 1 to 6, wherein the linker is selected fromcomprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, a urea, a sulfonamide, or a hydrazone bond.

8. The compound of any one of claims 1 to 6, wherein the linker is:wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -Cl-18 alkylaryl, or -alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

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

10. The compound of claim 9, wherein the PEG moiety is -(CH2-CEI2-O-)n-, and n is 5-30, or n is 10-15.

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

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

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

14. The compound of any one of claims 1 to 13, wherein the antibody or engineered biologic molecule is an anti-C3 antibody or engineered biologic molecule or an anti-C5 antibody or engineered biologic molecule.

15. The compound of 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, Vatalanib, LY2874455, and SU5402.

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

17. The compound of any one of claims 1 to 16, wherein: the antibody or engineered biologic molecule is pegcetacoplan, avacincaptad pegol, or avacincaptad pegol; and the small molecule is axitinib.

18. A compound comprising: a small molecule Complement inhibitor; an antibody or engineered biologic molecule, wherein the antibody or engineered biologic molecule is an inhibitor of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a linker that links the antibody or engineered biologic molecule to the small molecule, wherein the linker is cleavable in a mammalian ocular environment.

19. The compound of claim 18, wherein the Complement inhibitor is selected from a C3 inhibitor, a C3b inhibitor, a C5 inhibitor, a C5a inhibitor, a C5b inhibitor, a Factor B inhibitor, a Factor D inhibitor, a Factor H inhibitor, and a CD46 inhibitor.

20. The compound of any one of claims 18 or 19, wherein the antibody or engineered biologic molecule is a VEGF-A antibody or engineered biologic molecule.

21. The compound of any one of claims 18 to 20, wherein the antibody or engineered biologic molecule is selected from bevacizumab, ranibizumab, ramucirumab, brolucizumab, aflibercept, and conbercept.

22. The compound of any one of claims 18 to 21, wherein the mammalian ocular environment is selected from vitreous humor, a portion of a posterior segment of an eye, an ocular tissue, or an ocular cell.

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

24. The compound of any one of claims 18 to 22 wherein the linker is:wherein R is H, -Cl-18 alkyl, -aryl, heteroaryl, -C 1 - 18 alkylaryl, or -alkylheteroaryl, preferably, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, or benzyl.

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

26. The compound of claim 25, wherein the PEG moiety is -(CH2-CH2-O-)n-, and n is 5-30, or n is 10-15.

27. The compound of any one of claims 25 or 26, wherein the linker links the small molecule drug via the PEG moiety to the antibody or engineered biologic molecule.

28. The compound of 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 of claim 28, wherein the Complement inhibitor is avacopan, avacincaptad pegol, or pegcetacoplan.

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

31. A bispecific antibody or engineered biologic molecule compound comprising: a first antigen-binding site, wherein the first antigen-binding site binds a first target selected from at least a portion of VEGF, VEGFR, PDGF, PDGFR, FGF, or FGFR; and a second antigen-binding site, wherein the second antigen-binding site binds at least a portion of a complement protein selected from Factor B, Factor D, C5, C5a, CD46, and Factor H.

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

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

34. The compound of claim 33, wherein the PEG moiety is -(CH2-CH2-O-)n-, and n is 5-30, or n is 10-15.

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

36. The composition of claim 35, wherein the composition is an injectable ocular formulation.

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

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

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

40. The method of any one of claims 37 to 38 wherein the method is a method for treating an ocular disease comprising administering to an eye of a subject the compound of any one of claims 1-27 or the composition of any one of claims 28-31.

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

42. The method of claim 41, wherein the ocular disease is age-related maculardegeneration (AMD).

43. The method of claim 42, wherein the AMD is exudative AMD.

44. The method of claim 42, wherein the AMD is dry AMD.

45. The method of any one of claims 42 to 44, wherein the AMD is early stage AMD or intermediate stage AMD.

46. The method of any one of claims 42 to 44, wherein the AMD is late stage AMD.

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

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

49. The method of claim 48, wherein the subject experiences a reduction in the mean rate of change in square root GA area following administering the compound or composition.

50. The method of claim 48, wherein the subject experiences a slowing or stopping of GA growth.

51. The method of any one of claims 40 to 50, wherein administering comprises delivering or injecting into an eye of the subject via intravitreal, intracam eral, subretinal, or suprachoroidal delivery.

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