Methods and materials for treating ocular neovascular diseases

Abstract

Provided herein are methods of treating ocular neovascularization, e.g., associated with wet age-related macular degeneration (AMD) in a subject in need thereof, by targeting TNF-α and VEGF using combination therapies or bi-specific antibodies.

Description

[0001] Attorney Docket No.: 00633-0387WO1

[0002] METHODS AND MATERIALS FOR TREATING OCULAR NEOVASCULAR DISEASES CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No. 63 / 564,359, filed on March 12, 2024. The entire contents of the foregoing are incorporated herein by reference. SEQUENCE LISTING This instant application contains a Sequence Listing that has been submitted electronically as an XML file named “00633-0387WO1_ST26_SL.” The XML file, created on March 12, 2025, is 133,723 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This document relates to methods of treating ocular neovascularization by targeting TNF-α and VEGF. BACKGROUND Vascular endothelial growth factor (VEGF) inhibition has become the mainstay for the treatment of ocular neovascularization, especially in neovascular age related macular degeneration (AMD). However, most patients continue to progress to blindness despite exhausting all available therapeutic possibilities. Thus, there is an unmet need to treat ocular neovascularization. SUMMARY Provided herein bi-specific antibody molecules having (a) a first antigen binding domain binds to VEGF, and (b) a second antigen binding domain that binds to TNF-α, where the first antigen binding domain and the second antigen binding domains are linked together by a linker in any order. In some embodiments, the first antigen binding domain includes a light chain variable region (LC) sequence that is at least 90% identical to a LC amino acid sequence set forth in Table A, D, E, and H to P, and a heavy chain variable region (HC) sequence that is at least 90% identical to a HC amino acid sequence set forth in Table A, D, E, and H to P. In some embodiments, the second antigen binding domain Attorney Docket No.: 00633-0387WO1 includes a LC sequence that is at least 90% identical to a LC amino acid sequence set forth in Table B, D, E, and H to P and a HC sequence that is at least 90% identical to a HC amino acid sequence set forth in Table B, D, E, and H to P. In some embodiments, the bi-specific antibody molecule can include a combination of antibody or antigen binding domain thereof set forth in Table C, D, E, and H to P. In some embodiments, the bi-specific antibody molecules include optionally where the Fc is engineered to extend half-life and / or to silence antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In some embodiments, the bi-specific antibody includes amino acid sequences set forth in Tables D, E, and H to P. Also provided here are pharmaceutical compositions including the bi-specific antibody molecules and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutically acceptable carrier is a slow-release polymer. In some embodiments, the slow-release polymer is PLGA-PEG-PLGA triblock polymer, Poly(lactic-co-glycolic acid) (PLGA), Polyethylene glycol (PEG), Poly(ethylene oxide) (PEO), Poly(ethyleneimine) (PEI), Poly(l-lysine) (PLL), Poly(caprolactone) (PCL), Poly(vinyl alcohol) (PVA), Chitosan, Hyaluronic acid (HA), Poly(β-amino esters) (PBAEs), Poly(N-isopropylacrylamide) (PNIPAM), Poly(alkyl cyanoacrylates) (PACA), Poly(propylene sulfide) (PPS), Poly(ethylene glycol)-block- poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO or Pluronics), Poly(beta-amino esters) (PBAEs), Poly(ortho esters) (POEs), Poly(glycolic acid) (PGA), Poly(hydroxyethyl methacrylate) (PHEMA), or Poly(2-oxazoline) (POx), Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO- PEO or Pluronic). Also provided here are methods for treating ocular neovascularization in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a VEGF inhibitor and a TNF-α inhibitor. Also provided here are methods for treating ocular neovascularization in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a pharmaceutical composition including a bi-specific antibody molecule that targets both VEGF and TNF-α. Also provided here are nucleic acids encoding a bi-specific antibody described herein. Attorney Docket No.: 00633-0387WO1

[0003] In some embodiments, the subject is a mammal. In some embodiments, the subject has wet age-related macular degeneration, retinopathy, proliferative vitreoretinopathy, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, central serous chorioretinopathy, myopic macular degeneration, Coats’ disease, choroidal neovascularization, Posterior uveitis - Vogt-Koyanagi-Harada syndrome, uveitis, histoplasmosis-related choroiditis - ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, peripheral retinal neovascularization - sickle cell retinopathy / Eales’ disease, ocular trauma, corneal neovascularization, iris neovascularization - rubeosis iridis, ocular tumors, microangiopathy, neovascular glaucoma, corneal graft rejection, glaucoma, herpetic and infectious keratitis, ocular ischemia, neovascular glaucoma, corneal, uveal and iris neovascularization, conjunctivalization, stromal scaring, orbital and eyelid tumors, pterygium, Stevens Johnson Syndrome, ocular cicatricial pemphigoid, intraocular complications, ocular wounds or other ocular injuries, and ocular surface diseases. In some embodiments, the ocular injury includes (a) a chemical injury due to exposure to irritants, acids, or bases, (b) a surgical injury due to penetrating keratoplasty, keratoprosthesis surgery, glaucoma drainage device implantation or glaucoma bypass stent. In some embodiments, the retinopathy is selected from the group consisting of retinopathy of prematurity (ROP), diabetic retinopathy, retinal vein occlusion, sickle cell retinopathy, Stargardt’s disease, choroidal neovascularization, and radiation retinopathy. In some embodiments, the intraocular complication is a peripheral anterior synechiae, a proliferative vitreoretinopathy, an iatrogenic including ocular surgery or cyclophotocoagulation. In some embodiments, the VEGF inhibitor is selected from the group consisting of bevacizumab, ranibizumab, aflibercept, and brolucizumzb. In some embodiments, the TNF-α inhibitor selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. In some embodiments, administering is topical administration onto the eye. In some embodiments, administering is injecting at, into, or near the superior / inferior / nasal / temporal bulbar subconjunctival, intracorneal, intrastromal, Attorney Docket No.: 00633-0387WO1 intravitreal, intralimbal, subretinal, intraretinal, intralenticular, intrascleral, transscleral, suprachoroidal, intracameral, sub-bulbar, subtenon, orbit, or eyelid. In some embodiments, the treatment results in reduced or delayed ocular neovascularization. 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 this invention belongs. Methods and materials are described herein for use in the present invention; 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. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIGS.1A-1D. Characterization of 20% PLGA-PEG-PLGA triblock polymer. FIGS.1A-1B) Sol–gel transition from room temperature to 37 ℃. Note that the liquid polymer becomes a gel. FIG.1C) Molecular structure of the triblock polymer and FIG.1D) rheological assessment of the triblock polymer showing sol–gel transition peak at 37 ℃; n = 3. FIGS.2A-2N. In vivo evaluation of drug release following subconjunctival (superior bulbar) administration of the 20% triblock thermosensitive drug delivery system (DDS). FIG.2A) Schematic representation of the DDS containing antibodies injected in the superior subconjunctival space after corneal alkali burn. FIGS.2B– 2G) Biomicroscopic images of the upper conjunctiva and cornea harboring the DDS. The DDS slowly degraded, as evident by the regression of upper conjunctival thickening over 3 months. FIG.2H) ELISA analysis of aqueous humor samples demonstrated continuous release of therapeutic levels of antibodies (Abs: anti-TNF-α and anti-VEGF) in the anterior chamber for over 3 months. Likewise, IgG-DDS- treated (isotype control) eyes demonstrated a continuous release of human IgG in the anterior chamber for over 3 months. Three months after DDS injection, (FIG.2I) the subconjunctival tissue harboring the DDS was immunopositive for human IgG, Attorney Docket No.: 00633-0387WO1 suggesting the presence of humanized antibody in the tissue. Likewise, a humanized antibody was also found in the ciliary muscle (FIG.2J), iris (FIG.2K), and sub- retinal space (FIG.2L). FIG.2M) H&E staining of upper eyelid hosting the DDS showed no tissue abnormalities. The DDS appeared to be degraded and cleared from the tissue at 3 months. FIG.2N) No human IgG was present in the contralateral un- injected eyes of animals injected with either therapeutic antibodies or isotype IgG DDS; n = 3. FIGS.3A-3F. Anti-TNF-α / anti-VEGF DDS antibodies sustained released by thermogel DDS significantly halted the progression of corneal neovascularization after corneal burn injury. FIG.3A) Representative biomicroscopic images of burned DDS implanted rabbit eyes at specified time points. FIG.3B) Angio- graphic illustration of the corneas presented in FIG.3A. FIGS.3C-3D) CoNV area quantification in percentages of superior and inferior cornea areas, respectively. FIGS.3C-3C) Three months after injury, anti-TNF-α / anti- VEGF DDS conferred nearly complete blockade of CoNV (DTX curve). In contrast, eyes administrated with isotype IgG DDS exhibited extensive CoNV over 3 months (CoNV area at end- point: ~30% of superior area; 30% of inferior cornea) (IgG curve). Eyes treated with aflibercept DDS showed milder yet progressive CoNV when compared to the IgG DDS eyes during the 3-month follow-up (CoNV area at endpoint: ~15% of superior cornea; ~8% of inferior cornea). FIGS.3E and 3F) Biomicroscopic images and graph show nearly complete blockage of CoNV. Anti-TNF-α / anti-VEGF DDS antibodies were administered on day 1 and day 3 post burn. FIG.3F) Representative biomicroscopic images of alkali burned eyes, treated with isotype IgG-DDS subconjunctivally and anti-VEGF / TNF DDS at day 1 and 3 days after the injury. Eyes treated with isotype IgG DDS at day 1 post injury showed marked corneal opacity, stroma scarring, and neovascularization that were persistent. Eyes treated with anti- VEGF / TNF DDS at day 1 and day 3 post injury showed reduced corneal opacity and stromal scarring. At 2 months, there was a small corneal vessel in animals injected at day 1 with anti-VEGF / TNF therapy, which regressed at 3 months, whereas the animals treated at day 3 post burn showed no neovascularization. Mixed ANOVA; * p < 0.05; *** p < 0.001; n = 3. FIGS.4A-4C. Anti-TNF-α / anti-VEGF DDS treatment reduced corneal epithelial defect in the injured cornea. FIG.4A) Slit-lamp biomicroscopy of Attorney Docket No.: 00633-0387WO1 fluorescein-stained rabbit eyes implanted with different DDS. FIG.4B) Image reconstruction of corneal epithelial defects in the burned DDS-implanted corneas shown in FIG.4A. FIG.4C) Corneal-epithelial-defect quantification in percentage of total corneal area. Anti-TNF-α / anti- VEGF DDS treatment significantly suppressed the development of epithelial defect on the burned cornea, as compared to the aflibercept group and IgG groups; * p < 0.05; mixed ANOVA test with Tukey’s multiple comparison test; n = 3. FIGS.5A-5D. Corneal inflammation and leukocyte infiltration. FIG.5A and 5B) Marked CD45+ cell accumulation in the cornea of IgG-DDS-treated (FIG.5A) or aflibercept-DDS-treated (FIG.5B) eyes at 3 months of injury. FIG.5C) Remarkable reduction in CD45+ cell accumulation in the cornea following subconjunctival injection of anti-TNF-α / anti-VEGF DDS. FIG.5D) Quantification of the CD45 + cell number within the corneal tissue shows statistically significant reduction in the anti- TNF-α / anti-VEGF DDS group, as compared to control IgG DDS or anti-VEGF DDS groups; * p < 0.05 (one-way ANOVA with Tukey’s); ns: non-significant; n = 3. FIGS.6A-6L. Anti-TNF-α / anti-VEGF DDS treatment effectively ameliorated retinal neuropathy and optic nerve degeneration in the injured eyes. FIGS.6A–6D) Three months after corneal burn, IgG- or aflibercept- DDS-treated rabbits exhibited significant retinal ganglion cell loss, as indicated by a retinal ganglion cell marker β3- tubulin (red color). In contrast, the anti-TNF-α / anti-VEGF DDS provided almost complete protection against RGC loss. Arrowhead: a normal ganglion cell. FIGS.6E– 6G) Representative PPD staining of peripheral rabbit optic nerves (63× obj). (FIG. 6K) Loss of normal nerve axon in peripheral optic nerves relative to the contralateral intact optic nerve. (FIGS.6H–6J) Representative PPD staining of central rabbit optic nerves (63× obj). (FIG.6L) Loss of normal nerve axon loss in central optic nerves relative to the contralateral intact optic nerve. (FIGS.6E–6L) The protective effects of the anti-TNF-α / anti- VEGF DDS was confirmed with PPD staining of the optic nerves, which otherwise showed marked axonal degeneration in the IgG- and aflibercept-DDS-treated eyes and almost complete retention of the nerve axons in anti-TNF-α / anti-VEGF-DDS-treated eyes. One-way ANOVA with Tukey’s correction; * p < 0.005, ns: non-significant; n = 3. GCL = ganglion cell layer. INL = inner nuclear layer. ONL = outer nuclear layer. RGC = retinal ganglion cell. Attorney Docket No.: 00633-0387WO1

[0004] FIGS.7A-7D. Schematics illustrating different bi-specific. FIG.7A) This bi- specific antibody was produced using a Fab-scFv-Fc format antibodies (adapted from creativebiolabs.net / scfv-fab-fragments-bsab.htm). The Fc was engineered to extend the half-life and silence antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The bi-specific antibody is bivalent and thus, comprises one binding site for each antigen. FIG.7B-7D) Schematics illustrating knob-in-hole bi-specific antibodies. The bi-specific antibody can also include a Xencor mutation or LALAPA (L234A / L235A + P329A) mutation in the hinge region to reduce the immunogenicity of the antibody. FIGS.8A-8C. Evaluation of the protective effect of a Xencor bi-specific antibody in TNF alpha-induced cell death. FADD- Jurkat T cells were seeded at a density of 4 X 105cells / mL in a 96 well tissue culture plate. The cells were then treated with recombinant TNF alpha alone and TNF alpha + a Xencor bi-specific or mono-specific antibody pre-incubated at 37 ℃ for 30 minutes. The protective effect of antibody was evaluated using Alamar blue assay at 24 hours. The Alamar blue data shows high cell viability (increased fluorescence intensity). FIGS.8A-8C) The bi- specific antibody offered similar protection as the adalimumab at all concentrations: 1:2 ratio (FIG.8A), 1:4 (FIG.8B), and 1:6 (FIG.8C). IgG control treatment provided no protection against TNF alpha-induced cell death. FIG.9. Effects of a Xencor bi-specific antibody on VEGF-induced HUVEC proliferation. HUVECs (passage 3) were seeded at 5 X 104cells / mL in a 96-well tissue culture plate. Next day, 50 ng / mL of rhVEGF was pre-incubated with a range of bi-specific antibody concentration at 37 ℃ for 30 minutes in media without FBS and growth factors and added to the cells in 96 well plate. Forty-eight hours later, Alamar blue dye was added in each well, and the plate was incubated for 2 hours and read at 530nm excitation / 590nm emission. The Alamar blue data showed that 50ng / mL VEGF increased cell proliferation whereas the addition of bi-specific antibody inhibited cell proliferation due to binding of VEGF to the bi-specific antibody. The antibody at 1:2 molar ratio provided significant blockade of VEGF-induced endothelial cell growth. FIG 10: The Xencor bi-specific antibody provided similar protection as Avastin or Lucentis when used in the same equimolar ratio . Attorney Docket No.: 00633-0387WO1 FIGS.11A-11B: Binding affinities of the bi-specific antibody were tested using Enzyme linked immunosorbent assay (ELISA). FIG.11A) A knob-in-hole (KiH) bi- specific antibody with LALAPA mutation (Leu234Ala, Leu235Ala, Pro329Ala), when reconstituted in custom buffer showed similar binding affinities to the parental antibodies, Bevacizumab and adalimumab. FIG.11B) A bi-specific antibody with LALAPA mutation showed similar binding affinities to the parent antibodies. FIGS.12A-12D. Schematics of plasmids that were designed to produce bi- specific antibody in vivo. FIG.12A) The expression plasmid contains CMV enhancer and promoter followed by antibody expression cassette. The antibody cassette contains - CMV promoter -potential signal peptide, HC TNFa - linker- LC VEGF- linker - HC VEGF- IRES - Signal peptide -LC TNF-a. The plasmid also contains origin of replication, ampicillin resistance gene, PolyA tail, enhancer, lac, and SV40 promoter. FIG.12B) Plasmid similar to FIG.12A including a reporter molecule eGFP. FIGS.12C and 12D) Plasmids containing variable regions of adalimumab with reporter molecule mCherry and bevacizumab with reporter molecule eGFP. Each antibody can be encoded by separate plasmids, and both can be used to transfect the cells. FIGS.13A-13C. Bi-specific antibody encoding plasmids with (FIG.13A) Hif-1 promoter, (FIG.13B) Ang2 promoter, or (FIG.13C) VEGF promoter. These plasmids were designed using the bi-specific antibody with a Xencor mutation. DETAILED DESCRIPTION The present inventors have identified concomitant targeting of VEGF and TNF-α as an intervention for treating ocular neovascular diseases. As demonstrated herein, combination therapy with monoclonal antibodies against VEGF and TNF-α provides superior inhibition of neovascularization, as compared to predicate therapy with VEGF inhibitor. Furthermore, TNF-α inhibition is advantageous in reducing neovascularization, but not as effective as combination therapy using both VEGF and TNF-α inhibitors. The observed synergistic effect of VEGF and TNF alpha inhibitors against ocular neovascularization was unexpected and surprising. The resultant effect of concomitant inhibition of VEGF and TNF alpha exceeds dramatically the partial effect of each inhibitor alone and this outcome cannot be predicted by studying each inhibitor separately. Thus, the present disclosure includes methods for treating ocular Attorney Docket No.: 00633-0387WO1 neovascular diseases by a combination therapy using both VEGF and TNF-α inhibitors, or a bi-specific antibody targeting VEGF and TNF-α. Age-related Macular Degeneration and Other Conditions Advanced AMD is characterized as “atrophic” or “neovascular,” with the former showing loss of outer retinal layers, and the latter the presence of choroidal neovascularization (CNV). Neovascular (or “wet”) AMD is defined by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina. These blood vessels are immature in nature and leak fluid below or within the retina. The two forms of AMD can occur together and share pathologies of cell death and fibroglial replacement. Neovascular AMD accounts for 10 to 15% of AMD cases, develops abruptly, and rapidly leads to substantial loss of vision. Ocular injuries are often bilateral and can result in irreversible vision loss not only due to extensive corneal neovascularization (NV), conjunctivalization, and stromal scaring [1,2] but also due to intraocular complications, such as peripheral anterior synechiae (PAS), proliferative vitreoretinopathy (PVR) [3], and secondary or inflammatory glaucoma, with the latter a frequent and devastating long-term complication [4,5]. Although growth factors appear to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. Current standard of care for patients with CNV involves targeting the proangiogenic and permeability molecule vascular endothelial growth factor-A (VEGF) (Gragoudas et al., N. Engl. J. Med.351: 2805-2816 (2004); Ng et al., N. Y. Acad. Sci.1082:151-171 (2006); Rosenfeld et al., N. Engl. J. Med.355: 1419-1431 (2006)). However, although anti-VEGF therapy blocks vascular permeability and angiogenesis, it does not lead to complete vascular regression (Ng et al., N. Y. Acad. Sci.1082:151-171 (2006)). Moreover, in patients treated with VEGF antagonists, substantial vision improvement occurs in only one-third, with one-sixth of treated patients still progressing to legal blindness (Gragoudas et al., N. Engl. J. Med.351: 2805-2816 (2004); Rosenfeld et al., N. Engl. J. Med.355: 1419-1431 (2006)). Thus, there is an urgent need for safe nutritional or pharmacological interventions for the treatment and ideally the prevention of AMD. Attorney Docket No.: 00633-0387WO1

[0005] Vascular endothelial growth factor (VEGF) Vascular endothelial growth factor (VEGF) is a dimeric heparin-binding protein related to the PDGF / sis family of growth factors. It can induce angiogenesis and thus is a key contributor for embryonic development and wound healing. VEGF inhibitors, such as monoclonal anti-VEGF antibodies, have been proposed as an alternative to corticosteroids for the prevention and treatment of corneal neovascularization [7,8] in pre-clinical [9–11] and clinical studies [12–14]. However, antibody delivery to ocular tissues is a challenging task compared to other tissue targets, and it may lead to significant adverse events

[0018] . For example, systemic administration of antibodies, especially VEGF inhibitors, only offers limited drug availability in the ocular tissue, while it exposes the whole body to the agent and can lead to major complications. To minimize potential adverse effects, topical administration of antibodies in the form of eye drops has been attempted but was not shown to achieve adequate bioavailability in the eye [19,20]. Moreover, one study has shown that prolonged topical therapy with VEGF inhibitors can lead to epithelial toxicity [13,21]. The intravitreal administration of antibodies, on the other hand, achieves excellent bioavailability in the eye but has a limited therapeutic effect on the anterior eye and cornea and is associated with rare but devastating complications, such as endophthalmitis and retinal detachment. The subconjunctival administration of antibodies is an alternative option that allows for good drug bioavailability for both the anterior segment and the posterior segment [22,23]. However, antibodies undergo rapid diffusion in the subconjunctival compartment

[0022] compared to other competing drug elimination routes, thereby limiting the duration of the effect. Non-limiting examples of VEGF inhibitors includes bevacizumab, ranibizumab, aflibercept, and brolucizumab. (Table A). In some embodiments, the method includes inhibiting VEGF (e.g., VEGF-A, - B, -C, -D, PGF) and / or VEGFR (e.g., VEGFR-1, -2, -3) using antibodies. Examples include: Avastin (bevacizumab), a recombinant humanized monoclonal antibody that binds to VEGF-A and prevent interaction of VEGF-A to VEGFR-1 and VEGFR-2 (see, e.g., Presta et al., Cancer Res.57: 4593-4599 (1997); Hurwitz et al., N. Engl. J. Med.350:2335-2342) (2004); 2C3, a mouse monoclonal antibody against VEGF-A (Zhang et al., Angiogenesis.5:35-44 (2002); Brekken et al., Cancer Res.58: 1952-9 (1998)); IMC-1121B, a human monoclonal antibody against VEGFR-2 (Rockwell and Attorney Docket No.: 00633-0387WO1

[0006] Goldstein, U. S. Patent No.6,811,779); CDP-791, PEGylated, humanized di-Fab fragment that binds to VEGFR-2 (Ton et al., Clin. Cancer Res.13:7113-711 (2007)). Lucentis (ranibizumab) is a recombinant humanized monoclonal antibody that binds to VEGF-A, but its approved usage is for treatment of patients with neovascular age- related macular degeneration (available from Genentech). In some embodiments, the VEGF inhibitor is an anti-VEGF antibody or antigen-binding portions thereof (such as Fv, Fab, or scFv portions) to inhibit VEGF binding to KDR and / or flt receptors, e.g., Avastin® (Bevacizumab). Avastin is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human VEGF both in vitro and in vivo. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF (Presta et al., Cancer Res 57:4593-91997). Avastin is available from Genentech (South San Francisco, CA). See also: Schlaeppi and Wood, Cancer and Metastasis Rev.1999; 18:473-481; U.S. Pat. Nos.7,169,901; 7,056,509; and 7,297,334; U.S. Pat. Pub. No.20020032315; 20080187966; and 20090010883; and PCT No. WO 94 / 10202. In some embodiments, the antibody binds specifically to VEGF and block binding to VEGFR1, to VEGFR2, or block binding to both VEGFR1 and VEGFR2. Examples of antigen-binding domains include, without limitation, an antigen- binding fragment (Fab), a variable region of an antibody heavy (VH) chain, a variable region of a light (VL) chain, a single chain variable fragment (scFv), and a VEGF polypeptide. For example, an antigen-binding domain that targets a VEGF polypeptide can include a VEGF polypeptide amino acid sequence set forth in Tables A, D, E, and H to P. Tumor necrosis factor alpha (TNF-α) TNF-α is a homotrimer protein consisting of 157 amino acids, and regulates inflammatory responses. TNF-α inhibitors, including adalimumab and infliximab, were shown to provide significant neuroretinal protection against post-injury neuroinflammation in animal studies [8,15]. In some embodiments, the TNFα inhibitor includes infliximab, adalimumab, certolizumab pegol, CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti- TNF-α antibody fragment), or golimumab. In some embodiments, the TNFα inhibitor is a TNF fusion protein, e.g., etanercept. In some embodiments, Attorney Docket No.: 00633-0387WO1 the TNFα inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono) (Table B). In some embodiments, the TNF-α inhibitor is an anti-TNF-α antibody or antigen-binding portions thereof (such as Fv, Fab, or scFv portions) that can inhibit TNF-α binding to transmembrane TNF (tmTNF) and / or soluble TNF (solTNF) (e.g., infliximab). Infliximab is a chimeric bivalent IgG1 human-murine monoclonal antibody used to treat psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and plaque psoriasis. Adalimumab is a humanized bivalent mouse IgG1 monoclonal antibody used to treat ulcerative colitis, Crohn’s disease, psoriasis, psoriatic arthritis, spondylitis, rheumatoid arthritis, and polyarticular juvenile idiopathic arthritis. Certolizumab is a Fab’ fragment (lacks Fc region) of a humanized recombinant antibody against TNF which is used to treat rheumatoid arthritis. Golimumab is human monoclonal antibody against TNF used to treat rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Etanercept is a genetically engineered fusion protein comprising the Fc domain of human IgG1 fused to a dimer of the extracellular ligand binding domain of human TNFR2 / p75, and is used to treat rheumatoid arthritis, pediatric plaque psoriasis, psoriatic arthritis, plaque psoriasis, and juvenile idiopathic arthritis (Lis et al., Arch Med Sci 6:1175-852014). Examples of antigen-binding domains include, without limitation, an antigen- binding fragment (Fab), a variable region of an antibody heavy (VH) chain, a variable region of a light (VL) chain, a single chain variable fragment (scFv), and a TNF-α polypeptide. For example, an antigen-binding domain that targets a TNF-α polypeptide can include a TNF-α polypeptide amino acid sequence set forth in Tables B, D, E, and H to P. Methods of Treatment The methods described herein include methods for the treatment of disorders associated with ocular neovascularization. In some embodiments, the disorder is wet age-related macular degeneration (AMD), retinopathy, neovascular glaucoma, corneal graft rejection, glaucoma, herpetic and infectious keratitis, ocular ischemia, neovascular glaucoma, corneal, uveal and iris neovascularization, conjunctivalization, stromal scaring, orbital and eyelid tumors, Stevens Johnson Syndrome, ocular cicatricial pemphigoid, intraocular complications, wounds or other injuries (e.g., chemical injuries due to exposure to irritants, acids or bases or surgical injuries due to Attorney Docket No.: 00633-0387WO1 penetrating keratoplasty, keratoprosthesis surgery, glaucoma drainage device implantation or glaucoma bypass stent), and ocular surface diseases. In some embodiments, the disorder is associated with tumor neovascularization such as ocular cancer. In some embodiments, the disorder is associated with choroidal neovascularization (CNV), e.g., choroidal neovascularization secondary to, for example, the neovascular (wet) form of AMD, pathologic myopia, or ocular histoplasmosis syndrome. In some embodiments, the disorder is associated with retinal neovascularization (e.g., proliferative diabetic retinopathy). For example, retinopathy can include prematurity (ROP); diabetic retinopathy; retina vein occlusion; sickle cell retinopathy; Stargardt's disease; choroidal neovascularization; and radiation retinopathy. In some embodiments, the disorder is associated with surface neovascularization (e.g., secondary to a chemical or other injury, or Stevens-Johnson syndrome). In some embodiments, the intraocular complications includes a peripheral anterior synechiae, or a proliferative vitreoretinopathy. In some embodiments, the disorder is associated with tumor neovascularization, e.g., vasoproliferative ocular tumors (e.g., neoplastic and benign retinal vascular tumors such as retinal capillary hemangioma, hemangioblastomas, cavernous hemangiomas, Racemose Hemangioma (Wyburn–Mason Syndrome), Retinal Vasoproliferative Tumors, and tumors associated with Von Hippel–Lindau (VHL) disease; or choroidal vascular tumors including circumscribed choroidal hemangiomas and diffuse choroidal hemangiomas). See, e.g., Turell and Singh, Middle East Afr J Ophthalmol.2010 Jul-Sep; 17(3): 191–200. In some embodiments, the disorder will stem from overformation of blood vessels, or formation of blood vessels in an unwanted area, e.g., in the avascular regions of the eye, e.g., retinopathies, or in a tumor, e.g., a cancerous or benign tumor. For example, the ophthalmological disorder can be age-related macular degeneration (AMD), where new blood vessels grow under the retina, or retinopathy, e.g., diabetic retinopathy, where abnormal vessels grow on top of the retina. The disorder may stem from the formation of blood vessels that deliver blood to a tissue, e.g., a primary or metastatic cancerous or benign tumors, e.g., cancer. A metastatic tumor can arise from a multitude of primary tumor types, including but not limited to those of prostate, colon, lung, breast and liver origin. Attorney Docket No.: 00633-0387WO1 In some embodiments, the disorder is a cancer of the eye, e.g., eyelid tumors, e.g., malignant eye lid tumors, benign eye lid tumors, basal cell carcinoma, squamous cell carcinoma, sebaceous cell carcinoma, and malignant melanoma; conjunctival tumors, e.g., pigmented conjunctival tumors, melanoma and primary acquired melanosis with atypia, squamous conjunctival neoplasia, conjunctival lymphoma, and Kaposi's Sarcoma; iris tumors, e.g., iris melanoma, iris pigment epithelial cyst, anterior uveal metastasis, and pearl cyst of the iris; infiltrative intraocular tumors, e.g., multiple myeloma, lymphoma, and leukemia; choroidal tumors, e. g., choroidal melanoma, choroidal metastasis, choroidal nevus, choroidal hemangioma, choroidal osteoma, and Nevus of Ota; retinal tumors, e.g., retinoblastoma, retinal pigment epithelial tumors, retinal pigment epithelial hypertrophy, von Hippel angioma; optic nerve tumors, e.g., melanocytoma, melanoma, meningioma, circumpapillary metastasis; orbital tumors, e.g., lymphangioma, cavernous hemangioma, meningioma, mucocele, rhabdomyosarcoma, orbital pseudotumor, adenoid cystic carcinoma, periocular hemangioma of childhood; cancers of the ocular adnexa, e.g., lacrimal gland carcinomas such as adenoid cystic carcinoma and mucoepidermal epithelioma; and metastatic ocular tumors, e.g., metastatic choroidal melanoma, and metastatic retinoblastoma. In some embodiments, the disorder is associated with, e.g., vasoproliferative ocular tumors (e.g., neoplastic and benign retinal vascular tumors such as retinal capillary hemangioma, hemangioblastomas, cavernous hemangiomas, Racemose Hemangioma (Wyburn–Mason Syndrome), Retinal Vasoproliferative Tumors, and tumors associated with Von Hippel–Lindau (VHL) disease; or choroidal vascular tumors including circumscribed choroidal hemangiomas and diffuse choroidal hemangiomas). See, e.g., Turell and Singh, Middle East Afr J Ophthalmol. 2010 Jul-Sep; 17(3): 191–200. In this embodiment, the disorder is typically a wound, including both accidental as well as intentional wounds (e.g., surgical wounds), including ophthalmological wounds and injuries. For example, the injury can be a chemical injury due to exposure to irritants, acids, or bases, or can be surgical such as penetrating keratoplasty, keratoprosthesis surgery, glaucoma drainage device implantation or glaucoma bypass stent. In addition, the methods described herein include methods for the treatment of disorders associated with inflammation or “leaky” vasculature. Ocular inflammatory Attorney Docket No.: 00633-0387WO1 conditions that may be treated with the methods described herein include, but are not limited to, endophthalmitis (e.g., the endogenous form and the exogenous form), macular edema (e.g., macular edema that occurs as a result of age-related macular degeneration, cataract surgery, diabetes, drug toxicity, eye injury, retinal vein occlusion (e.g., central retinal vein occlusion (CRVO) and branch retinal vein occlusion), or other inflammatory eye diseases, e.g., pseudophakic macular edema), conjunctivitis, episcleritis, keratitis, optic neuritis, orbital pseudotumor, retinal vasculitis, scleritis, and uveitis (e.g., (i) uveitis associated with sepsis (e.g., LPS- induced uveitis); (ii) autoimmune uveitis (e.g., uveitis associated with lupus); or (iii) uveitis associated with type II, type III, type IV, or type V hypersensitivity reactions). See, e.g., WO2011133964 and WO2013003467. In some embodiments, the methods described herein include methods for the treatment of disorders associated with neovascular glaucoma or iritis due to surgery or photo-therapy (laser photocoagulation). Methods for treating ocular neovascularization can include identifying a subject (e.g., mammal) as having ocular neovascularization. In some embodiments, the treatment is administered to a subject who has been diagnosed with a disorder associated with ocular neovascularization; such a diagnosis can be made by a skilled practitioner using known methods and ordinary skill. In some embodiments, the methods include a step of diagnosing or identifying or selecting a subject with a disorder associated with ocular neovascularization, or identifying or selecting a subject based on the presence or a diagnosis of a disorder associated with ocular neovascularization. Non-limiting examples of methods of identifying the subject as having ocular neovascularization includes eye exam, optical coherence tomography, fluorescein, indocyanine green angiography, fundoscopy, ultrasound imaging, other imaging methods that may require contrast agent (e.g., magnetic resonance angiography, computed tomography angiography x-ray, or digital subtraction angiography), and / or positron emission tomography. Combination Therapies – Anti-VEGF and Anti-TNF-α Provided herein are methods for treating ocular neovascularization in a subject (e.g., mammal) in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a VEGF inhibitor and a TNF-α inhibitor. In some embodiments, the subject is a mammal (e.g., Attorney Docket No.: 00633-0387WO1 mice, or human). In some embodiments, the VEGF inhibitor is selected from the group consisting of bevacizumab, ranibizumab, aflibercept, and brolucizumab. In some embodiments, the TNF-α inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. In cases where a TNF-α inhibitor provided herein and a VEGF inhibitor provided here are provided separately, the administration of a TNF-α inhibitor provided herein can be in any order relative to the administration a VEGF inhibitor provided here. For example, a TNF-α inhibitor provided herein can be administered to a subject prior to, concurrent with, or following administration of a VEGF inhibitor to the subject. In some embodiments, the methods include co-administering VEGF inhibitor and a TNF-α inhibitor to a subject. Methods for treating ocular neovascularization using a combination therapy of a VEGF inhibitor and a TNF-α inhibitor as provided herein can be effective to reduce or delay ocular neovascularization, or to reduce or delay progression of ocular neovascularization. In some embodiments, treating ocular neovascularization in a subject in need thereof can be effective to eliminate ocular neovascularization in the subject. In some embodiments, the treatment is administered to a subject who has been diagnosed with a disorder associated with ocular neovascularization; such a diagnosis can be made by a skilled practitioner using known methods and ordinary skill. In some embodiments, the methods include a step of diagnosing or identifying or selecting a subject with a disorder associated with ocular neovascularization, or identifying or selecting a subject based on the presence or a diagnosis of a disorder associated with ocular neovascularization. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, an effective amount is one that achieves a desired therapeutic effect, e.g., an amount necessary to treat a disease, or to reduce risk of development of disease or disease symptoms (also referred to as a therapeutically effective amount or a prophylactically effective amount, respectively). An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. For example, a therapeutically effective amount of a bi-specific antibody molecule provided herein, or a combination Attorney Docket No.: 00633-0387WO1 of a VEGF inhibitor and a TNF-α inhibitor can be effective to reduce the ocular neovascularization in a mammal (e.g., human). The bi-specific antibody molecule provided herein, or a combination of a VEGF inhibitor and a TNF-α inhibitor can be administered one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments. Various factors can influence the actual amount used for a particular application. For example, the frequency of administration, duration of treatment, combination of other agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in the actual amount administered. The frequency of administration of bi-specific antibody molecule provided herein, or a combination of a VEGF inhibitor and a TNF-α inhibitor provided herein can be any frequency. For example, the frequency of administration can be from about four times a day to about once a month, or more specifically, from about twice a day to about once a week. In addition, the frequency of administration can remain constant or can be variable during the duration of treatment. As with the amount administered, various factors can influence the actual frequency of administration used for a particular application. For example, the amount (dose), duration of treatment, combination of agents, site of administration, stage of disease (if present), and the anatomical configuration of the treated area may require an increase or decrease in administration frequency. For example, the methods can include administering a first dose, followed by a second dose at a later time (e.g., a “booster” dose), e.g., at 1, 2, 4, 6, 8, 12, 18, 24, or 52 weeks later or any other time recommended by a treating physician. Administration of the combination therapy can involve non-overlapping injections of the two inhibitors, such as administration of a VEGF inhibitor on day 1, followed by administration of a TNF-α inhibitor on a different day. The frequency and spacing between the VEGF inhibitor and the TNF-α inhibitor can be adjusted according to the therapeutic requirements. For example, the Attorney Docket No.: 00633-0387WO1 VEGF inhibitor can be administered more frequently (e.g., every 3 weeks), and the TNF-α inhibitor can be administered less frequently (e.g., every 6 weeks) and vice versa. Dosage, toxicity and therapeutic efficacy of the therapeutic compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit high therapeutic indices are preferred. While compositions that exhibit toxic side effects may be used, care should be taken to minimize and reduce side effects. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compositions used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models. Such information can be used to more accurately determine useful doses in humans. Examples of routes of administration include systemic parenteral, e.g., intravenous, intraperitoneal, intradermal, or subcutaneous; local to the eye, e.g., topical, intravitreal, intraocular, intraorbital, periorbital, subconjuctival, subretinal, subtenons or transscleral; and systemic oral administration. In some embodiments, intraocular administration or administration by eye drops, ointments, creams, gels, or lotions may be used, inter alia. In some embodiments, the bi-specific antibody molecule provided herein, or a combination of a VEGF inhibitor and a TNF-α inhibitor provided herein are administered systemically (e.g., orally). In some embodiments, the bi-specific antibody molecule provided herein, or a combination of a VEGF inhibitor and a TNF-α inhibitor provided herein are administered to the eye, e.g., via topical (eye drops, lotions, or ointments) administration, or by local injection, e.g., periocular or intravitreal injection; see, e.g., Gaudana et al., AAPS J.12(3):348– 360 (2010); Fischer et al., Eur J Ophthalmol.21 Suppl 6:S20-6 (2011). Attorney Docket No.: 00633-0387WO1 Administration may be provided as a periodic bolus (for example, intravitreally or intravenously) or as continuous infusion from an internal reservoir (for example, from an implant disposed at an intra- or extra-ocular location (see, U.S. Patent Nos. 5,443,505 and 5,766,242)) or from an external reservoir (for example, from an intravenous bag, or a contact lens slow-release formulation system). The bi-specific antibody molecule provided herein, or a combination of a VEGF inhibitor and a TNF- α inhibitor provided herein may be administered locally, for example, by continuous release from a sustained release drug delivery device immobilized to an inner wall of the eye or via targeted transscleral controlled release into the choroid (see, for example, PCT / US00 / 00207, PCT / US02 / 14279, PCT / US2004 / 004625, Ambati et al. (2000) Invest. Ophthalmol. Vis. Sci.41:1181-1185, and Ambati et al (2000) Invest. Ophthalmol. Vis. Sci.41:1186-1191). A variety of devices suitable for administering agents locally to the inside of the eye are known in the art. For example, administration may be provided as injecting at, into, or near the superior / inferior / nasal / temporal bulbar subconjunctival, intracorneal, intrastromal, intravitreal, intralimbal, subretinal, intraretinal, intralenticular, intrascleral, transscleral, suprachoroidal, intracameral, sub-bulbar, subtenon, orbit, or eyelid. See, for example, U.S. Patent Nos.6,251,090, 6,299,895, 6,416,777, 6,413,540, and 6,375,972, and PCT / US00 / 28187. Bi-specific Antibodies Provided herein are bi-specific antibody molecules including a first antigen binding domain binds to VEGF; and a second antigen binding domain that binds to TNF-α, where the first antigen binding domain and the second antigen binding domains are linked together by a linker, and can be in any order. Non-limiting examples of linkers can include heterobifunctional linkers, homobifunctional linkers, peptide linkers, cleavable linkers, spacer linkers, non-covalent linkers, click chemistry linkers, cleavable disulfide linkers, hydrolysable ester linkers, thermosensitive linkers, photoactivatable linkers, biological affinity-based linkers, or polymer linkers. In some embodiments, a polymer linker is a polyethylene glycol (PEG), dendrimers, poly(amino acids), poly(N-isopropylacrylamide), and poly(lactic-co-glycolic acid) (PLGA). For example, the bi-specific antibody molecules can include sequences of bevacizumab for VEGF inhibition and adalimumab for TNF-α inhibition. In some embodiments, the bi-specific antibody molecules are produced using cell lines (e.g., Attorney Docket No.: 00633-0387WO1 human embryonic kidney cell line). For example, a bi-specific antibody molecule containing the amino acid sequence set forth in SEQ ID NO: 9 can include 3 G4S linkers. In some embodiments, the first antigen binding domain includes a light chain variable region (LC) comprising a sequence that is at least 90% identical to a LC amino acid sequence set forth in Tables A,D, or E, and a heavy chain variable region (HC) comprising a sequence that is at least 90% identical to a HC amino acid sequence set forth in Tables A, D, or E. In some embodiments, the second antigen binding domain comprises a LC comprising a sequence that is at least 90% identical to a LC amino acid sequence set forth in Tables B, D, or E and a HC comprising a sequence that is at least 90% identical to a HC amino acid sequence set forth in Tables B, D, or E. In some embodiments, the bi-specific antibody molecules comprise a combination of antibody or antigen binding domain thereof set forth in Table C, D, E, and H to P. The bi-specific antibody can include Fab-scFv-Fc regions, optionally where the Fc is engineered to extend half-life and / or to silence ADCC and CDC. In some embodiments, the ADCC and CDC do not need silencing to induce immune activation. Also provided herein are methods for treating ocular neovascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a bi- specific antibody molecule that targets both VEGF and TNF-α. In some embodiments, the subject is a mammal. The constant region of an antibody (e.g., a bi-specific antibody molecule described herein) mediates several effector functions, and these effector functions can vary depending on the isotype of the antibody. In addition, the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR). There are a number of Fc receptors which are specific for different classes of antibody, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors) and IgM (mu receptors). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody- coated particles, clearance of immune complexes, lysis of antibody-coated target cells Attorney Docket No.: 00633-0387WO1 by killer cells (called antibody-dependent cell cytotoxicity or ADCC), cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement- dependent cytotoxicity (CDC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production. In some embodiments, an antibody comprises a variant Fc region. The amino acid sequences of the Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (e.g., a representative human IgG1 Fc region is shown in Lobner et al., Immunol Rev. 2016 Mar; 270(1): 113–131). In some cases, Fc regions with amino acid variations have been identified in native antibodies. In some embodiments, a variant Fc region is engineered with substitutions at specific amino acid positions as compared to a native Fc region. In some embodiments, the Fc region is mutated to alter (reduce) antibody dependent cell-mediated cytotoxicity (ADCC), antibody induced complement dependent cytotoxicity (CDC), and / or antibody dependent cell-mediated phagocytosis (ADCP) (see, e.g., Kang and Jung, Experimental & Molecular Medicine.2019.51:1– 9; Wang et al., Antibody Therapeutics, January 2021.4 (1):45–54; Lobner et al., Immunol Rev.2016 Mar; 270(1): 113–131). In some embodiments, the Fc region is afucosylated (see, e.g., Yamane-Ohnuki and Satoh, MAbs.2009 May-Jun; 1(3): 230– 236, which describes methods for production of therapeutic antibodies with controlled levels of fucosylation of Fc region N-glycans). In some embodiments, the one or more constant regions of a bi-specific antibody molecule described herein has / have been modified. In some embodiments, the antibodies (e.g., a bi-specific antibody molecule described herein) may comprise modifications to one or more of the three heavy chain constant regions (CH1, CH2 or CH3) and / or to the light chain constant region (CL). In some embodiments, the heavy chain constant region of the modified antibodies (e.g., a modified bi-specific antibody molecule described herein) comprises at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibodies comprises more than one human constant region. In some embodiments, modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or more regions. In some embodiments, one or more regions are partially or entirely deleted from the constant regions of the modified antibodies. In some embodiments, the entire CH2 domain has been removed from an antibody (ΔCH2 constructs). In some embodiments, a deleted constant region is replaced by a short Attorney Docket No.: 00633-0387WO1 amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region. In some embodiments, a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody. In some embodiments, a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and / or CH3 domains. In some embodiments, modified antibodies (e.g., modified Fc region in a bi- specific antibody molecule described herein) provide for altered effector functions that, in turn, affect the biological profile of the antibody. For example, in some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region enhances Fc receptor binding of the modified antibody as it circulates. In some embodiments, the constant region modifications increase the serum half-life of the antibody. In some embodiments, the constant region modifications reduce the serum half-life of the antibody. In some embodiments, the constant region modifications increase or enhance ADCC and / or complement dependent cytotoxicity (CDC) of the antibody. In some embodiments, the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties. In some embodiments, the constant region is modified to add / substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites. In some embodiments, the bi-specific antibody molecule is produced using antibody formats well known in the art. For example, the bi-specific antibody can be produced using a Fab-scFv-Fc format, an scFvTNF-α – scFvVEGF format, a Fab-Ds- scFv format, or a CrossMAbVH-VLformat. In some embodiments, the bi-specific antibody described herein comprises a Xencor mutation, LALAPA mutation, or a knob-in-hole mutation. A Xencor mutation or a LALAPA mutation can reduce the immunogenicity of the Fc domain region of the bi-specific antibody. In some embodiments, a knob-in-hole bi-specific antibody comprises a Xencor mutation. Moore (2019. Methods 154:38-50) discloses exemplary methods for generating bi-specific antibodies containing a Xencor mutation (XmAb®), and is incorporated herein by reference. In some embodiments, a “sweeping antibody” is created by modifying the constant region to increase binding to an FcRn at neutral pH (e.g., human IgG1 mutations T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, Attorney Docket No.: 00633-0387WO1 M252Y / N286E / N434Y, or M252Y / V308P / N434Y mutations) or increased affinity to FcγRIIb (e.g., human IgG1 mutations P238D or E233D / G237D / P238D / H268D / P271G / A330R), resulting in increased clearance of the antibody’s target from the body (see, e.g., (Igawa et al., 2016)). Other amino acid substitutions that increase binding to a membrane bound receptor are known in the art (see, e.g., Kamat, et al. (2022) Analytical Biochemistry 640:114455). Amino acid substitutions can include any one or more of: E233D, L234A, L235A, G237A, G237D, P238D, T250Q, S267E, L328F, M252Y, S254T, T256E, H268D, N286E, P271G, V308P, A330R, M428L, H433K, N434S, N434Y, N434A, N434F, and combinations thereof, as well as T250Q / M428L, M252Y / S254T / T256E, M428L / N434S, M252Y / N286E / N434Y, M252Y / V308P / N434Y, H433K / N434F, M252Y / N434F, S267E / L328F, or E233D / G237D / P238D / H268D / P271G / A330R. In some embodiments, the bi-specific antibody molecules described herein comprise one or more constant heavy domains (e.g., CH1, CH2 and / or CH3 regions). In some embodiments, the bi-specific antibody molecules described herein comprise a constant heavy domain 1 (CH1) having an amino acid sequence set forth herein, e.g., in Table G. In some embodiments, the bi-specific antibody molecules described herein comprise a constant heavy domain 2 (CH2) comprising an amino acid sequence set forth herein, e.g., in Table G. In some embodiments, the bi-specific antibody molecules described herein comprise a constant heavy domain 3 (CH3) comprising an amino acid sequence set forth herein, e.g., in Table G. Modifications to the constant region of antibodies described herein can be made using well known biochemical or molecular engineering techniques. In some embodiments, antibody variants are prepared by introducing appropriate nucleotide changes into the encoding DNA, and / or by synthesis of the desired antibody or polypeptide. Using these antibody variants, it may be possible to enhance the activity or effector function provided by a specific sequence or region while substantially maintaining the structure, binding activity, and other desired characteristics of the modified antibody. Exemplary sequences of anti-VEGF are shown in Tables A, D, E, and H to P. Exemplary sequences for anti-TNF-α are shown in Tables B, D, E, and H to P. Exemplary combinations for bi-specific antibodies against VEGF and TNF-α are shown in Table C. Exemplary sequences for anti-TNF-α × anti-VEGF bi-specific Attorney Docket No.: 00633-0387WO1 antibodies are shown in Tables D, E, and H to P. Exemplary sequences for promoters that can be used to design a bi-specific antibody described herein are shown in TableF. Exemplary sequences for constant region are shown in Tale G. Exemplarysequences for variable regions of anti-TNF-α and anti-VEGF are shown in Table H. Tables M-P also include amino acid sequences comprising mutation sites, deamidation sites, oxidation sites, N-glycosylation sites, linker, LALAPA (L234A / L235A + P329A) mutations in the Fc domain, substitution of EEM with DEL, disulfide bond (VH44-VL100) at the interaction interface to enhance molecular stability, and 4 G4S linkers to provide greater flexibility. Table A: Anti-VEGF Antibodies Light chain Heavy chain G K H T V A I H L Y S TL I G ID G G S Y S H G S Attorney Docket No.: 00633-0387WO1 Light chain Heavy chain E lea (Afliberce t) SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIP N L V D E F Q L T G D H

[0007] Attorney Docket No.: 00633-0387WO1 Table B: Anti-TNF-α Antibodies Light chain Heavy chain Et t LPA VAFTPYAPEPGSTCRLREYYD TA MCCSKCSPG HAKVFCTKTS C F P P Y N S S G R A ST AP S S V F T SL A L T SL T G V T N P K V F G W T Y L T LS K Attorney Docket No.: 00633-0387WO1 Light chain Heavy chain Golimumab EIVITOSPATLSLSPERATLSCR QVOLVESGGGVVOPGRSIRLSCAASGF Y L G K Y S K P C A WI G K D C Q

[0008] Attorney Docket No.: 00633-0387WO1 Table C: Combinations for bi-specific antibodies Anti-VEGF Anti-TNF-αBevacizumab Etanercept s , Attorney Docket No.: 00633-0387WO1 Table D: Full length sequences of custom Anti- TNF-α × Anti-VEGF bi- specific antibody (Fab-scFv-Fc) with Xencor mutation Heavy chain 1 (HC1): VH (anti-TNF)-CH1-CH2-CH3 SEQ ID NO: 16 MHSSALLCCLVLLTGVRA (signal peptide S S D S F V K V S V L L P E H R L S L T P T T G E N T D Attorney Docket No.: 00633-0387WO1 (signal peptide + TSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTL anti- VTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCSASQ VEGFsequence) DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTI Y V W bi- specific antibody (Fab-scFv-Fc) with knob-in-hole mutations HC1 (KiH MW: 49.38 kDa, 451 aa) SEQ ID NO: 25 MKHLWFFLLLVAAPRWVLSEVQLVESG ([1:19] Signal peptide; GGLVQPGRSLRLSCAASGFTFDDYAMH [20:139] VH anti-TNFalpha; ) 0 a; Attorney Docket No.: 00633-0387WO1 LSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC cts SEQ ID NO: 28 AAAGCCCATTCCCTCTTTAGCCAGAGCCGGGGTGTGCAGACGGCA (VEGF promoter GTCACTAGGGGGCGCTCGGCCACCACAGGGAAGCTGGGTGAATGG sequence) AGCGAGCAGCGTCTTCGAGAGTGAGGACGTGTGTGTCTGTGTGGG G C A T G G G T T G C C G T C T T T A A A A A G T C G Table G: Exemplary constant region sequences Antibody Fragment Sequence G V D D N L Attorney Docket No.: 00633-0387WO1

[0009] TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 31) G V D D N L G V D D N L 3) G V D D N L G V D D N L 5) G V D N L G V D D N L G V D N L Attorney Docket No.: 00633-0387WO1 TVDKSRWQQGNVFSCSVMHEALHYHYTQKSLSLSPGK (SEQ ID NO: 38) G V D N L G V D D N L G V D D N L 1) G V D D N L G V D D N L 3) G V D D N L G V D D N L Attorney Docket No.: 00633-0387WO1 TVDKSRWQQGNVFSCSVMHEALHWHYTQKSLSLSPGK (SEQ ID NO: 45) G V D D N L G V D D N L E A E M S V G P V C D E G P E S T PS V D D N G N N V Attorney Docket No.: 00633-0387WO1 Table H: Exemplary full length sequences of variable regions of anti- TNF-α and anti-VEGF bi-specific antibody (scFvTNF-α – scFvVEGF) ATGCACAGCTCAGCACTGCTCTGTTGCCTGGTCCTCCTGACTGG GGTGAGGGCCGAGGTGCAGCTGGTGGAGAGCGGCGGCGGACTGGT GCAGCCAGGAAGGAGCCTGAGACTGAGCTGCGCCGCCAGCGGCTTC T T G G G G A A A T C G G A G G T C C A A C G C G A Attorney Docket No.: 00633-0387WO1 SAL TTAL P AAS GNTSRYSGSS SI IQ DSL C TLT KV I LLGFLLG QKSQ)9TKTF TE WYH5 R L WMQ L MQKIL E NYESK SG G QTF E TVL V KGGVQ L WQIDG QWDPGPWYV EAD DYDV FSKWTKPDWP E DE VVS NGTKVQRATLSQLTGL SGP Y PIL L VCSYGGCP HQDKS L KKWGYSGF WL SSK GGS GPTHGNG SSDS ISF LNVGP VQ F TFFTKY VKL AFLFT GA SGDRWSVVKGFY SQL GGQSP P E SSH E RSYGSP V PSIKGN V F G V TYGA T TV H L V WF HSSVSADVKADS P GCGYVE REC L QNR S RTPHYISDA V YGIHQPSTP L L E E M K K G T L Q A V S A S V H DI AVCL KAS SR L F HRL GVH VQVSNKS T L FGSSTL A V P NPPDE K E CPSD P E VLSG NGAFV VRKL WTK SN QATNAVP TE L Q AWMGT ATQ HCPVKY VKT WGICCTE Y ASY CIL AYYGVYPT SGTPVKKV GQIDYH SS L L D VSL TSQC A P STTTE NNE SL N PFR NSL HP THL RFSH L W SE KSK ASSAG L T WP Y L S RVDQF GA RL ATPGSKSIE GDE GGN P KDSSL ANSD VQGKSH L P CMGHKVD)7QGRYP W SL VPSSVKTDL VAL L M5KVV:L AI SF T TVVVVPDV E YTSC ISWPCO GQF KST GRRAPVV K L SVP WVTL P STSFND GVGCGPKKNSK T ESKPF VE VKVISWE YK TPLSDPKVIE VF F PQYNQ N GE VHSY VS YV L MDAAY SDL L VRAN KF E YPKNQS(T P TL TE Q QAATSKGSVDSA P K VYYDVVSNSP E NKMQWG E D D E T L QSPE G H Y N E GRSP S L V--sH D V -_bvaF Fcs Attorney Docket No.: 00633-0387WO1 SAL AASTT GAL P NTSRYSGSDS SI IK SL CGTSYGF AYKSGQQ PIHKL I HQGTYVNWE TL E MVGT QSYTASL E YSS E R(VSRSCG GGP T SE DSTVN SK VD L V G WKGDTY F YG GY GAGE T ATAKWQE D P DDPVVPS VIT ASYRV V GCT SLLLKPYQE RAITLLSAVFS DGLNI ST SKNGPHP D F WL QSKSLS P E GR P GL W QLNVGPV GMGFFTKY K LSSAQSS Q KL L GGVL WVVVAF L GF Q F T P K SGS PSGG I GP W VSE Y ADPEGP SK SY VSIK VGH Q QLFD T N TKTGVCTYAE VKADQL MQTKILSV RE CSH L E GKKWPHYISD QIYF GSHPSTPL L A DVGP T W T K G A DS VS S E D SA P D NA P VV P H DI AVCL KAS SR KL F HRL GVH VQVSNS S T L FGSSTL APNVPPDE K VE CPP E D VLSGNNGA QFV RKL WTK S AWM A GTTNAVP HCI PVKYTE L Q E YVKT ATCIQ L WGV CCT V AYYG YASY SGSTPPTKKIY CVAGQDL H SS L L DTTQTE NP SFN RVSL S T P NL E PFH L WNSKL GHTH RYSL SE KSASRL ATSA PGLT SKRSVWP F G E DQG A DE GGNSPKDL ASNSSDIL P CMVQG H S SL GL KK H VDM)0QGRYP WV TD AL LV 6VPSL AI SF STKVVKCV:TVVVVPDYTSP SO GQF KST E K LIWP CNP VVP WVTL TSGRRAVSK GVGCGP SKPNSKS E TFD VKVIS E WE YKE L K VYTPFSDPF V F KVIPQYNQ GE VHSVSYYV L MD L L VRANN F E YPKNQS(AASD K P TL TE Q QAATSKGTVDSA P K VYYDVVSSNSP E NKM W E Q G E D D E T L QSPG H Y N E GRSP S H V--sL D V -_bvaF Fcs Attorney Docket No.: 00633-0387WO1 CP SQAL SL:TGO CP SRA TITAGQA SCVCQ L SQN TIAGSQ CA V VK GGYTV VAS L H TDITK VGGSYT )t)R α DP SF YR TKSNS DYV E Q RP FYTR K F KRAIA E TVTCE DK S QRSAIE ecV SSneRQQIAK YL TRTA TKP MP KLVQ P V SSITWSAL DA KAIP KA RQHTV u ) D TL S SQGDPTE VKGTDTDE YL L T qeF GW TN GVL L VC NSCKSTVHK D S S VASF YA RSGsGSTVSK VSTPD PHKSHVK V AM G EPKTMG VWSTF Y Q E SL A AD S A TQKTP P SP NCPVVE Y RE KSE YF YL KVP SS SN L TF D TQ yrVASY C NYa- IGISE F E KP TVSPTKD HPVVYKIR TSGN NSCL A S)SYYIGC litL nS RILSY L GYVSF HTKTPGT TKSYVVHKFV G VDS NNK EPIP KE Y VPLSFLS 36L N :S SILSY VGY paSGKS P DVL CV L L L QFVKSDKST m(P e1SQP GAT SVGAKGSSNDF SVCVTYY P T QWAYCGFSNQO PSQP GSAF x C QSA TAKF L DQPVT L L L NSSPV E WEDPW L VLNSGGTNQYD QSA AKF D E H : MRGRSEPGJ QCP PF FS VCAYCIKP GPNF EQ RHAQP SE DSQHIT MSGRSEPITKVQTSG P L GSL YE TVAT RKPL KE VWD NQ CP P QE L W EQITK Q elDIT Q GL SY P G A NG S Q KV PSIVKV E T TN SR P N V VRH S LS(DIV T Q GL S ba- F T N T L - - V L -VH - H V V F babaN mTsF m-ssF oGsroG ErE C V C V Attorney Docket No.: 00633-0387WO1 L SL:GO CQT L SQ V SHND TS VTVSTP S T E P TVSE ATVDQQ)8L STQ VL QVGVYNKKSMAIL VQT6TKGSP VT SE GKAEVPWYG TNQNITE E DP WY:QP PSSP RHO P ALK DPE L KR TSNG P RFESPN AF F WL YTSSVSKE WITKH KAPIVRPYP DP PFKDL DIYPFDHP VTCM L EP KQAPL GYVAQ D L VKV V TNP TDTH TKNTE E L L NL HS SSG SPL SVSP P CDE KVAYV VAEKM(GCT LVSKTKPHSATKQCPSVVK A TKG L ASHH N KV L N H SPSQ L GL SGP STAGLSNT KP DVVSVE RSNF CSS L S YAASYV P NDF VE VKP VSFF L ESS SSTN SG LCIC VVVCQQ V SLF G G L V GW SGSV RKGNW NS V Y K V C D Y Y K K EDSG K TTSQ SGVL GDP THHVKAE P KTMGASGSSTVLVCDSVV RYKE YYL F KVPTVPASP SKP STPKPVE YESIR NSSS CKDVTKTSGLP N KE YCSSKISE F TPNSTP VG DSGKP VP L F LS)EKPF V HPHPF V NN LEIL L QFFV7VSST P YVVKT HKL VV F CYY P T QWAYCG NSNK6GGQ:K DGV D T E DPW TO TAKSSN GLCV W V SVNE QL QLSE DQYNQPVT F L LSL V NSP EP F RHAP S SQHD CASCKGTKP L KE VWD QE L WNIGFVGYIP E ARVK TVNRP NVVRSHQ TSG P L SL YVVSIE KTSVQKAPL KEWGANGT SQKPP P L MDAVKGTIP A DTDES(P K A W S T K A L E N S C K M S T V H K Attorney Docket No.: 00633-0387WO1 Table K: Exemplary sequences for anti- TNF-α × anti-VEGF bi-specific antibody containing KiH mutations and modifications to prevent aggregation (Fab-Fc-scFv format) HC1 (KiH MW: 49.38 kDa, 451 aa) SEQ ID NO: 71 MKHLWFFLLLVAAPRWVLSEVQLVESG [1:19] Signal peptide; GGLVQPGRSLRLSCAASGFTFDDYAMH [20:139] VH anti-TNFalpha; a; Attorney Docket No.: 00633-0387WO1 Table L: Exemplary sequences for anti- TNF-α × anti-VEGF bi-specific antibody containing Xencor mutations and modifications to prevent aggregation HC1: Signal peptide-VH (anti-TNF)-CH1-CH2-CH3 SEQ ID NO: 74 MHSSALLCCLVLLTGVRA (signal peptide F V K V S V L LI L T S L G A T K L L P L L R L S Attorney Docket No.: 00633-0387WO1 ediflS SN SP usQWF YSPWLS i TARRPQSS L d MLSPQ CFIVY KTG gQnIY NVYFVASQ i DRDH sIGY ir)GSTSPE RKT)TGQAAPSV78p α F SQL GSTVAYDVFDE QC:O tn23G T V E66V L RE SYSSS L TH GVSAL TSE Y V VPE TK aP V×, -i3F L t T LISCDP SGAKTG F CPHQ GSKPWL Q T I GKLSYGSGP DGGVE E CLTE K VSY α- A n La(CGSPGPF K TAGLSKTF TADRK P YY CGSQGAV VAIVH L N F A2QAFS P SWEVKE H NLC W GVQRYSSQ P TKQD FL L RRY YGPV PS FT- ,H VQSVACKGE P SA i M G V K V T T W G T P T A N R Y treG E n k a ni)r lWP E L WAL NF F T 6 QL S LK YK AYLo6VGNYAV TASPVKFSVVf SSKGFQ T s4 3eGTL KKDGP KP ESKFY , GG L F GP VITVSH A GP ASGNSSTH THNGDV L G AE RKCDN cn aert 92 GSA QDA RTSVV NAHSYEI SH P WDL ux3P E R VSIS LKSGSCIE T P VSALSL A E qees e ,nAL V WTFYSSPT L YADNA V TP VYL VPH ht o5Q 3 VHR AA GVL C QAQPM GQP VEKNT TV g,d2L E M SAE K APFST GP VE K S CC NTKC)ne n,lAHYVSCVN SLTRS Y WSTVPVL NS5F8lolb4VD 3 GDDY AYPSSSH K TE TKE:DNVO u2L TF VGVP P CREN ATYAKTVKTKKSPGNf(yr)TFD TV α AGITSP TDRA CSINY E PP Q D GQIalF VSHD GE ASE VS P VKMHKL QQ V TNWE p NLASASFSPL GSS T-FA i L CNR L VYSLE TENYE R(VDVL VWS mt IISWSTDSKG QE KK ex na(CL SRTINV L K VYK LKPDW DP E VDGP E: 1C WL AMTL DKVQRAGSSQGCGVP YHPIV TS L M RVL QSS P W QDL S H G KF L e M G W Y G L Q T L N V GSPKSL S lbaL TV--sH D V -_bvaF Fcs Attorney Docket No.: 00633-0387WO1 S N SP QWSF YSWL S TARRPPQSS F YL MLSPQ CIV KTG 2 L8SSA VQRYVF E T D KS (6)3WCSF G L L TDGL RKYTLF P SK NRN SSDK LTIF E GGVFVV DN DAL VE YSP E V TQ F,L TYP GGW S VP L T GSIQ G ATTPHQKL W Y E66VV RLKVLISNAD E GGSVE CTE VKSH V-i3W t T L DKSSE E M VVGYAQ GG E DRKYAVN n L GPITKL YTPR A a L WAVP YVIL EQD FHL ( TVSA KL TQNE LSVE VK TKP SPFSA)2 DA T GF GV CETFG TNDP V CKGE RYGE98C TS E L P D STFA ANP F H:KTG YM GY YP T L D H F TQ VN QGSMO MS S Q G T G G N L WC P E H W G K D V N ) W P E L F TK 6 QL LSWA VNF KL AYFY L K Q 63VGNYASDTAPVSVVKGFT P P ESS FY T L KKL G , GGASGF K THGP VIKSDVTVGH A GP NSS9GADATHNG VAE RKL EICDN SH 2SQ TSVNAHYP WDL 3 P E RRSSK GCE STLL A , V A L VITL YSSSTIP VSA YADNASVE P H 5 QWF S PL TP VYL VP32VHRVAAQCVQAQTM L E MGKL GTP VE KNTV , SAEPS P CE NKKS)AHYVAFSCVNG L C 4 VDSTTRPST C8VL YS 832G DYSW YPSSSHVK E NF :TE KDNVO L TDF A GVP P TC TYVKT KTKKRSEPN GN( A ) TFDIA TTSVVDRAY P TCSNE P QQDIα AGHD F VS NLAGSE AE VSIP ASP V FS KPMHKL GQQ L VGTNSWE T-FAS SiL CNRVYL E TE NYE RS(DVL V S tIISWL TDSV G QWKK na(CL SRTS I NV L K VYKKW KPDDP E E VDGP 1 A WL MTL L DKVQAVS SS GCGP Y RPITL C G Q RVLSVP HQDL S H QGSKF WL M G W Y G L Q T L N V GSPKSL S H V--sL D V -_bvaF Fcs Attorney Docket No.: 00633-0387WO1 htiSR DQGL TI N SS F L QSAG SRQSSSw)Gt) PGYHSIWPVSL L AYY a α VV TVRGD P GYQIL T SWLST L V TP C VNSKNF VVSW L ATTF WAN L S TTrFSA DD AVVKHS K)WAL S AFm N L SYFYSSK L SY D o L L DQVAK E T4L L NAT fT-itL SNS YITQT D V9RTW YP:L SR YIGn VSPILGCK GQQ EDSO VSPILS cneu DRK Gqe ,GC sA TP SRTL L VSP TERWKDAIDGL DSKGQSAASPP DPP DERDL QS GC TPSQ Q 4)TIAGWSTKSCAAGSKCKDKQISSVQK TIAG GYSSTSL HTPE THPPPPQ STKSC ht 3g2L6GVG(6P3VRPSDKFY GNSNHK HKL APYPWT) GVGGY RTKIY EGeSWL VT KP SP VA NVAL F T L T RY GTS1 PRPSY H9VDKFT n l)TWGQSAVSGNDFD T L AYKKKN:WGQRAlF,L QPVKTSVSCICL VH KVVYD O LSFlGALVYVDT TSYSF VVVNQL NVHLNLVQPD ufE9V2LSy-i 3VAWGE K SP GSVQ SP L TKVVE SSP C QPSNT D LSYVE CVVVE E L AIVAWGP rt PS an ,WL A QQPEVTE P TGV SL QRWP L LGAPAVG DRKPL QKE S SHQ WL NSQ SL HL lap(AL 5 LSPY SF13NTSSITLF P YPG FLGV SKAE VYC TKQS VGYME VS(L LSPYLSSS2 L TS QRIATYPF DT VKHSK SDAP TYSYG WNE KQN LNS FFSL SNS ICK TQSITT m C L DTGAL ASV PVEP RNYKA ES SGDTDFL exH T E MQYTF RP L VVKSIF GKKWGFPT QYITF E:MQI S IL DNGCGSTTAP Q MKE NSTE VS E MSL A L TILDNL S MQID Y K G T V N C L V E L T E VSA V T NeL - L - lb V-Va H - H V F F TbV aG N EbamTssVms- F o-rFsNorG E C T C V Attorney Docket No.: 00633-0387WO1 PSAPCNS V KFSRAVDD VKH KK) , L A)SASP KGV VDGCVTAS LP AIDSF K 532VS VAT TL TVATE L VVAPL DSSDVGPL7,0T 4 AVKAV SK L NSVG VTE E GV TPL A4YLGSGSSSNP P D NYYVG TVVSVFPQS 3,T A GTNSA RV GPSLPP RYY Q TQLS28WL( 6Q 3 GKS S SYKCP SIWTKP K CE VTWK KRQ LSVL H T NPM CLNSFNKRP AYST )α,W FSYPG AVSVTTKYY E QCSNKY NDH N66DL P ESNHDVQ QCTK EE KGLSE VN)6T-i3LSPFPIF L YKP PE GK NAVP TL H9:tT,SVYVTDKPDR E P L KQQ L NGKAO na AAS A TP DPQC TSPFHKWSIKNSVEN(922SGKFTGKSTDTSHD P L VKQKTEL IC3L PYKV TL HLSE F DAHE L I E WFFM VQ HSSCV VVVNL V A G GSSKS H VPDE A R VSSE P V G CS(TSL L VSP TEPRWKDAIDGL , A AASPP D P DEDL S 4)A SKC DKIRSSVQK 32W SSA TGSLSHTKPE QP HTHAPPPQQ L6KGNYNH TKSKL APL YFPWT TR (6)3 IY)5T EGVSWSL VPGNKPFVA DNV TL TGTS AY H9KKK:F,TVSCIDL VHL NO GAK TSKTSYCSF VVVKVVYD NQL NVHLNE9V2GSVP QL TKV-SVE S VVSP E CNTADIi3P QSPEVQP TE P C V E L TGVRWPKE t,GPA G DRKPL HQ nFAF GVGV YC SQSE a(A5TLPYPFLSKAE V Q P YTK VGYM VS(132WF DT K SYG KSDATWNE KQNSLF SK C LPH VVTSH P V L VSP VEP RNYKAN KEFSCSGSVKSIF GK W FPSGCGTTAP MKQ E NSTE GVS Y K G T V N C L V E LIL T E VDSNL S Attorney Docket No.: 00633-0387WO1 -baSmuQIQAITGQ DCQSE QKAEQIIQATGQ DC E QKA z DS i AYIL F TTDV KSYS(DS AYIL F TTDV KSY b G i TRL F CLYSD P P AQV G KC TRL L FYSD P P AQV K na )STαGP IKD TPTAPFE RE E SC THTAGRI IKD P P TAFE RE H SNFPVKGGGRIE RPTASNFPT VK R F VVK VYSNVVK VYSE n,G eAu9GVE YSNGSQVPK GYSGS2 VADGS SGVE KP WT L Q GVE VADGN SSGV q3GSWVASes P,E HSSKS PADE CL E KT GSWVASSKS PAD VMDTVV L QKAVRKT YVSY E HS DTVV L QKAV ADTCL HEP VP KYVAIYH N VMADTCL HE V hA5L AYE VGVN VAVTE KQDL L F H AYE VGVNP VAV tg3Q n2Y VDDA I RL TL A APC NP CTKGP S E P F L QY S VDDA I RL TL A APC NP T eLE HLFCVAN Y A E HLFCCV l,SD G ll A)HF S ATIP R TGSNQ PENL P F GE SD G F S ATIPPEGTHYCPHWQGDH)HTGSNQ GTHYCPu 4f32W6VF NM GVT GGQTTVDGKSM99VF NM GVT QTT WQWGySGTHRE D QKVLV:GGWQWGSGTHR rL(63TSa)T AATIL Y YDTSSTGTSIV ALSO TSL L KMGH L KCVPCNAATIL Y YDTSSTGTSIL L KM l α TAAp F AC N VSSLSLSKASDL DVSWPSF D TAALLSKASDL V SSGSSCTVTITL TVIACSSS V SSGSCT L L N KASPSP SDYL KSTNQ V L L NASPSSP SD me T- FRW xitL L E ATANVKPKPWVE VKGEFRWK ATANVKPKE nIISL S NLLWTE NSIPQYQS(L L E L SLWTEP:a(CRGDYPSVVKP F VANNQKIIS NL GPSVVKP O1SGKRSF VVKP KVAKN E WG CR DY KRSF VVKP C WP GSVVSTSKF VRL T L P RP SGP GSVVSTSKF l QPIKPVSL DL E Y F P TAE QSS WQPIKPVSDL e H G AT GPSV SK L G TPL F b V F A E VD DGKS VAF AG SV a M L Q R C K P Y K S E N N R N D L M L Q R C KE P Y KV S T L V H - -VsH - - L D V_sD V -v -_bFbvacaF FsFcs Attorney Docket No.: 00633-0387WO1 QE HO T VNEDI,SL VE 6 W 6QR 3 DPWS T QE E KK G , HRVDP A L PAIV TS 92VQDL LS 3 TG KSKLPL P S AYVS,VASKF L K Q 5)VS32VVIGF T TKF Y L7,04R YKVS E AGH N A4Y3,TISP CDSSH DL 2AL8NAL (6YASL A L VE )3Q V F L E AQPH E KNPM G RN TV)E P SKTTS30V- KVL KC1itTKE YS:KCDNFO na(AKRNE VN2 NYSP ND HEPPQGIC VKL GQQ H E GT V N YNQE S WS(,YS S S A9QVSPE VK 2 E KP WTQ 3 E CL E L T P R , P KTVKY YYASH A K 53TE VIYN KQDLF H 2 KGP SP F L L ANE YSA , NL RF GE)A4)H P GDH232WVWQS6E DGKDM01QKVLV:L(63V ALSO ) T GH CVC α DL KPPSND F VVSTIW L TFIN Y T TV T L -iW tVKS E VKNQ NSIQYGESn F VPNNQ(a(KVAKNQK 1 VRATE WG E YL L P RP C P TAE QSS H DSKDGKLS E N N R N D L Attorney Docket No.: 00633-0387WO1 -bam SRQGL TI N SS F L QSAG SR S DQSSIuGD P GYHSIWPVSL L AYY TVRGPGYQ L T zib)WL TVP C i α VVSL T VNSKNF VVSW L ATTF WSN AL S TTSA DD AVVKHS K)WAL S AFnaN L T LSYF FDYSK8L SY D QVAKSE T0L L AT R(-itLLSNS YITQTTWDYV1P:L SN RYIGn VSPILGCR KGQQ EDSO VSPILS ecneDR u,GCK GqTP SRTL L VSP TERWKDAIDGL DSKGQ GQSAASPP DPP DERDL QS GCPSQ eA4)TSIA TKSCAAGSKCKDKQISSVQK TTYSSTSLHTPE THPPPPQ)SIAG TKSC s3h2W6GVGG tL(6P3VRPSDKFY GNSNHK HKL APYPWT5 G GGY RTKIY EGWL VT KP SP VA NVAL F T L T RY GTS0 PVPSY H1VRKFT gn)TWGQSAVS SGNDFD TAYKKKN:WDQRAeF,L Q l GALVPV T KSVSCICL VHL KVVYD O L GSFYVDT TSYSF VVVNQL NVHNL VQPD llE92LSVAWGEKSP GSVQT SP L KVVE SSP L C QPSNT D L SYVE CVVVE E L AIVAWGP u V f -i 3tPS , WL A QQPEVTE P TGV SL QRWP L LGAPAVG DRKPL QKE S SHQ WLNSQ L HL yrnaal(AL 5 LSPY SF13NTSSITLF P YPG FLGV SKAE VYC TKQS E VGYM VS(L LSSYLSSSI2L TS QRIATYF DT LPVKHSK SDAP TYSYG WNE KQN LNS FFSL P NSCK TSSITT p C L DTGATA mSV PVEP RNYKA ES SGDQDFL H T eQYIF RP L VVKSIF GKKWGFPTTQYITF x E M MQI SL DNGCGA L TSTTAP Q MKE NSIT L EDVS L E L QSL D Y K G T V N C L V E L T E VSN S MIA V T E:P L - - eVL -Vl H - H b VbF VbF a AG N

[0010] T E A MTssVMs- F o-rFsNorG E C T C V Attorney Docket No.: 00633-0387WO1 PSAPCNS V DKFSRAVD VKH KK)2 Q L D W S T Q E A LDI,A G 5)S QI DP SK P RAISVS 3VWP P E L Y TCSF V H L DAL ASPDDNL 27L,0YA 4 DL P V F AQKF VNVA L P LSL GS P VQLLP AYSF YPT DFGPE V L SVHT VL ATYPVP VE VKYF PQSK 4,SVTS C SNVGTWQ 32A8ASK P VHSKG GTV TR GVSQKKST)0L(63TSGL V )αL,L KCGSPK DAV E DVVPE VYKY H1YTGSVVAP VRK A D1E T YCRCN N:FSSSL TT L VK Y P TP R TKQSNV E THO N66VASAAVNAPSIWS NNYLE GSP L L ANT-i3tTK ASA VTGS SSSPCMFYKKVQKSE DIn,CTGNL P L KQ AQG H SKP TV G NNV Q a(A9YVGSWYHC E DE E NK LSKSLF ME VS 223YL VTTS NT P VL VHKDRIWTTE F(SS C P H GSTG P P KL W CK A T QKSVSNT S C KKE KD E E G P H T QEID V DSFGPT LSP TERAL , SL V AAASPP DPDP W DK E DIDG I RDL QS A)AGSKCKKQ SSV K 4S3 WSTSLSHTPE HTHP APPPPQ P Q WT)26KGNYNHKSKL Y9L(6)3 IGWL VTPPVAVAL F T L T RY GTS01FTE , VSKTSNK SVGSCIDFDNT CL VHL AYKKKH KV N:VYD O GATSYSF VVVNQ HNE9TK 2 GSVP QTKVVE S VSP L NVL CNTAD V-i 3QSL t PEVQPSTE P CV GVVE RWE LIP E nP,GaFAPF AGVGT VDRK CPLKHQ SQSE (A5TLPYPFLKG AE VY TKQVGYM VS(132WF DTSSK P YSYG DATW E KQNSLF SK C LPH VVTSKH P V L VSP VEP R N N N YKA EFSCSGSVKSIF GKKW FPSGCGTTAP MKQ E NSTE GVS Y K G T V N C L V E LIL T E VDSNL S Attorney Docket No.: 00633-0387WO1

[0011] Exemplary sequences In some embodiments, the sequence of a protein or nucleic acid used in a composition or method described herein is at least 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to a sequence set forth herein. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 80% of the length of the reference sequence, and in some embodiments is at least 90% or 100%. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available on the world wide web at gcg.com), using the default parameters, e.g., a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. In some embodiments, the sequence of a protein or nucleic acid used in a composition or method described herein has up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions as compared to a sequence set forth herein. In some embodiments, the substitutions are conservative substitutions. Preferably, the substitutions are outside of any CDRs. Attorney Docket No.: 00633-0387WO1 Pharmaceutical Compositions Provided herein are pharmaceutical compositions that comprise a VEGF inhibitor and a TNF-α inhibitor, or a bi-specific antibody, or one or more nucleic acids (e.g., one nucleic acid or two nucleic acids) encoding a bi-specific antibody as described herein, that can be used in the methods described herein. In some embodiments, compositions comprise a bi-specific molecule and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is a slow-release polymer. In some embodiments, the slow-release polymer is PLGA- PEG-PLGA triblock polymer, Poly(lactic-co-glycolic acid) (PLGA), Polyethylene glycol (PEG), Poly(ethylene oxide) (PEO), Poly(ethyleneimine) (PEI), Poly(l-lysine) (PLL), Poly(caprolactone) (PCL), Poly(vinyl alcohol) (PVA), Chitosan, Hyaluronic acid (HA), Poly(β-amino esters) (PBAEs), Poly(N-isopropylacrylamide) (PNIPAM), Poly(alkyl cyanoacrylates) (PACA), Poly(propylene sulfide) (PPS), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO or Pluronics), Poly(beta-amino esters) (PBAEs), Poly(ortho esters) (POEs), Poly(glycolic acid) (PGA), Poly(hydroxyethyl methacrylate) (PHEMA), Poly(2- oxazoline) (POx), or Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO or Pluronic). In some embodiments, the nucleic acid comprises an origin of replication, a resistance gene (e.g., ampicillin resistance gene), a PolyA tail, an enhancer (e.g., SV40 enhancer, or a gene specific enhancer), a lac, a promoter (e.g., SV40 promoter), and antibody expression cassette. For example, the antibody expression cassette can include a CMV promoter, a potential signal peptide, a HC TNF-α, a linker, LC VEGF, a linker, a HC VEGF, an IRES, a signal peptide, and a LC TNF-a. In some cases, a linker can be a flexible linker, rich in small or hydrophilic amino acids (e.g., stretch of Gly and Ser residues (“GS” linker)), a rigid linker, a helical structure or rich in Proline (e.g., (EAAAK)n, (XP)n) linker, an in vivo cleavable linker, a reductive or enzymatic cleavage disulfide, or a protease sensitive sequence. In some embodiments, a promoter is a Hif-1 promoter, an Ang2 promoter, or a VEGF promoter. Also provided herein are pharmaceutical compositions that comprise a vector containing one or more nucleic acids (e.g., one nucleic acid or two nucleic acids) described herein. In some embodiments, the nucleic acid is in a vector. In some embodiments, the vector is a viral vector or a non-viral vector. In some embodiments, Attorney Docket No.: 00633-0387WO1 the viral vector includes a lentivirus, an AAV, an adenovirus, an adeno-associated virus, retrovirus, or a herpes simplex virus. In some embodiments, the non-viral vector is a liposome, exosome, an extracellular vesicle, a polymer, a nanoparticle, a peptide, or a dendrimer (See e.g., US 2023 / 0338580 A1). For example, a non-viral vector can be a lipid nanoparticle (LNP). As used herein the language “pharmaceutically acceptable carrier” includes saline, buffers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Pharmaceutical compositions are typically formulated to be compatible with an intended route of administration and with the type and concentration of the drug they carry. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, intratumoral, intramuscular or subcutaneous administration. Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions used for parenteral, intradermal, intramuscular, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, lyophilized powder, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the Attorney Docket No.: 00633-0387WO1 extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. Nanoparticles (1 to 1,000 nm) and microparticles (1 to 1,000 μm), e.g., nanospheres and microspheres and nanocapsules and microcapsules, can also be used. These can Attorney Docket No.: 00633-0387WO1 be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No.4,522,811; Bourges et al., Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Opth Vis Sci 44:3562–9 (2003); Bourges et al., Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev 58:1182–1202 (2006); Ghate et al., Ocular drug delivery. Expert Opin Drug Deliv 3:275–87 (2006); and Short, Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations. Toxicol Pathol 36(1):49-62 (2008). A microporous drug delivery system (DDS) can also be used, e.g., comprising a porous polydimethylsiloxane (PDMS) scaffold (see, e.g., C. Zhou, et al., Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye. Transl. Vis. Sci. Technol.9, 5 (2020)), or porous polydimethylsiloxane / polyvinyl alcohol (see, e.g., C. Zhou, et al., Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye. Investig. Ophthalmol. Vis. Sci.58, 96–105 (2017)). In some embodiments, the carrier comprises a polymer, e.g., a hydrogel, that increases retention of the compound in the eye and provides local and sustained release of the active ingredient. Such polymers and hydrogels are known in the art, see, e.g., Paulson et al., Laryngoscope.2008 Apr;118(4):706-11 (describing a chitosan-glycerophosphate (CGP)-hydrogel based drug delivery system); other carriers can include thermo-reversible triblock copolymer poloxamer 407 (see, e.g., Wang et al., Audiol Neurootol.2009;14(6):393-401. Epub 2009 Nov 16, and Wang et al., Laryngoscope.2011 Feb;121(2):385-91); poloxamer-based hydrogels such as the one used in OTO-104 (see, e.g., GB2459910; Wang et al., Audiol Neurotol 2009;14:393-401; and Piu et al., Otol Neurotol.2011 Jan;32(1):171-9); Pluronic F- 127 (see, e.g., Escobar-Chavez et al., J Pharm Pharm Sci.2006;9(3):339-5); Pluronic F68, F88, or F108; a poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly (lactide-co- glycolide) triblock copolymers, or polyoxyethylene-polyoxypropylene triblock copolymer (e.g., a polymer composed of polyoxypropylene and polyoxyethylene, of general formula E106 P70 E106; see GB2459910, US20110319377 and US20100273864); MPEG-PCL diblock copolymers (Hyun et al., Biomacromolecules.2007 Apr;8(4):1093-100. Epub 2007 Feb 28); hyaluronic acid hydrogels (Borden et al., Audiol Neurootol.2011;16(1):1-11); foams, e.g., as Attorney Docket No.: 00633-0387WO1 described in WO2009132050A9, WO2011049958A2, WO2015031393A1, or WO2010048095A2; gelfoam cubes (see, e.g., Havenith et al., Hearing Research, February 2011; 272(1–2):168–177); and gelatin hydrogels (see, e.g., Inaoka et al., Acta Otolaryngol.2009 Apr;129(4):453-7); other biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Tunable self-assembling hydrogels made from natural amino acids L and D can also be used, e.g., as described in Hauser et al e.g. Ac-LD6-COOH (L) e.g. Biotechnol Adv.2012 May- Jun;30(3):593-603. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. In some embodiments, the composition (e.g., in foam or gel form) is injected into the eye. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Materials and Methods The following methods were used in Examples 1-5 below. Thermosensitive Polymer Solution Preparation To generate a thermosensitive, injectable, biodegradable hydrogel for the delivery of therapeutic biologics, a poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly (lactide-co- glycolide) triblock copolymer was dissolved (15:1 lactic acid: glycolic acid, 1750–1500–1750 Da) (AK141, PolysciTech, West Lafayette, IN, USA) in sterile water (20% w / v) at 4 ◦C overnight, with gentle stirring, as suggested by the manufacturer’s user guide

[0025] . The polymer solution was then sterilized with 30 min ultraviolet light radiation in a biosafety hood. The sterile polymer solution was stored in syringes at −20 ℃ until use. To prepare the drug-loaded polymer solution, infliximab lyophilized powder (Janssen biotech, Raritan, NJ, USA) was weighed and dissolved in the sterile polymer solution at 4℃, which is the storage temperature for the antibodies. The aflibercept Attorney Docket No.: 00633-0387WO1 injection solution (Regeneron, Tarrytown, NY, USA) was added to the solution at 4 ℃. The final product contained 2 mg of therapeutic proteins (1:2 infliximab:aflibercept) in every 300 µL of polymer solution (refilled in a 1 mL Luer- Lok syringe (309628, BD, San Jose, CA, USA). Rheology Test The rheological properties of the 20% triblock polymer were measured with dynamic mechanical analyzer (Discovery HR-3, TA instruments, New Castle, DE, USA) with a 20 mm 5-degree cone. The test was performed by oscillating at an angular frequency constant 6.283 rad / s, 0.1% strain, in increments of 1 ◦C, ranging from 4 to 45 ℃, with 1 min of temperature equilibration at each temperature, as suggested by the manufacturer. Corneal Neovascularization Model A corneal alkali injury was used to generate corneal NV, as previously published [7,8,15,18,26–29]. Rabbits were treated in accordance with the Association for Research in Vision and Ophthalmology Statement on the Use of Animals in Ophthalmic and Vision Research and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The protocol was approved by the Animal Care Committee of the Massachusetts Eye and Ear (ACC 10-033A). Dutch-Belted rabbits (n = 10, female, 2–2.5 kg) purchased from Envigo, Dedham, MA, USA, received an intramuscular injection of ketamine hydrochloride INJ, USP (35 mg / kg; KetaVed, VEDCO, St. Joseph, MO, USA) and xylazine (5 mg / kg; AnaSed, LLOYD, Shenandoah, IA, USA) prior to surgery. Then, 0.5% proparacaine hydrochloride (Bausch & Lomb, Tampa, FL, USA) was used for topical anesthesia to the eye before commencing alkali burn, using an 8 mm diameter filter paper soaked in 2N NaOH, applied to the center of the cornea for 20 s. After the burn, the eye was irrigated with normal saline for 15 min, as described also in prior published papers by our group (refs. [7,18,26]). Subconjunctival DDS Placement Each 20% triblock polymer was UV-radiated for 30 min on ice and then mixed with either a predetermined amount of infliximab dry powder, aflibercept stock solution, or both. The drug-laden triblock polymer solution was distributed in 1 mL syringes for in vivo injection. Each syringe was prefilled with 300 µL of drug-laden DDS and was stored at 4 ℃ until animal injection in vivo. Attorney Docket No.: 00633-0387WO1

[0012] For DDS administration, chilled DDS (300 µL / syringe / injection) loaded either with 2 mg of infliximab / aflibercept antibodies (1:2) (n = 3), 1.3 mg of aflibercept (n = 3), or 2 mg of human IgG isotype (n = 4) (I4506-100 MG, Millipore-Sigma, Saint Louis, MO, USA) were injected at the superior bulbar subconjunctiva of eyes immediately after the post-alkali exposure irrigation, i.e., 15 min after the injury. Erythromycin ophthalmic ointment (0.5%, Bausch & Lomb, Tampa, FL, USA) was administered topically twice a day for 1 week. Evaluation of Corneal NV and Epithelial Defects An evaluation of the corneal NV was performed under general anesthesia every week for the first month and every two weeks thereafter for two additional months. Eyes were photographed with a digital SLR camera (Nikon, Melville, NY, USA) attached to a surgical microscope (S21; Carl Zeiss, Jena, Germany). A portable slit-lamp (Keeler 3010- P-2001; Keeler Americas, Malvern, PA, USA) with a cobalt blue filter was used to assess corneal epithelial defects with fluorescein staining at 10× magnification. ImageJ 1.50e software (http: / / imagej.nih.gov / ij / (accessed on 28 August 2021); National Institutes of Health [NIH], Bethesda, MD, USA) was used to analyze the images. Epithelial defect was quantified as the percentage (%) of the total corneal area stained with fluorescein (pixel2) normalized to the whole cornea area (pixel2) [18,29]. Corneal NV was quantified separately for the superior and inferior cornea as the vascularized area in each half normalized to half of the corneal area (%). Illustration graphs of all the representative biomicroscopic images of corneal neovascularization and epithelial defects were manually sketched in Adobe Illustrator 2020 software (Adobe, San Jose, CA, USA) by delineating the corneal vessels and defects with a ‘pencil’ tool on top of the original photos. Aqueous Humor Collection and ELISA Assay The rabbit’s aqueous humor (AH) was collected when the animal was under general anesthesia at prespecified time points. Tropicamide ophthalmic solution (USP 1%, Akorn, Gurnee, IL, USA) and topical anesthetic (0.5% proparacaine hydrochloride, Bausch & Lomb, Tampa, FL, USA) were applied to the eye. A 30G needle combined with a 1 mL syringe was used to aspirate approximately 50~70 µL aqueous humor from the treated eye and the contralateral eye. Antibiotics eye drops were given to the eye following the procedure. Aqueous humor samples were stored Attorney Docket No.: 00633-0387WO1 in a −80 ℃ freezer until processed with ELISA assay. All AH samples were diluted in PBS at 1:20 and stored on ice. Human IgG sandwich ELISA assay (RAB0001, Sigma, Saint Louis, MO, USA) was performed per manufacturer’s protocol. Serially diluted human IgG standards and blank samples were analyzed along with the test samples. A standard curve was generated to calculate the human IgG concentrations in the AH. Human IgG levels were quantified in the AH of rabbits injected with IgG- and antibody-loaded DDS. Histological and Immunohistochemical Evaluation of the Cornea Rabbits were euthanized at 3 months, using intravenous Beuthanasia-D (sodium pen- tobarbital and phenytoin sodium, 100 mg / kg; Merck Animal Health, Madison, NJ, USA). Eyes were dissected and fixed in 4% paraformaldehyde (PFA). One half of the globes was embedded in optimal compound temperature (OCT, Sakura Fineteck, Torrance, CA, USA) for frozen tissue sections (10 µm thickness), using a cryostat (CM1950; Leica Biosystems, Buffalo Grove, IL, USA). The other half was embedded in methacrylate for tissue sections for histologic evaluation with hematoxylin and eosin (H&E) staining. Immunohistochemical assays were performed as previously described

[0026] . Primary antibodies were diluted in 1% BSA and incubated with tissue sections overnight at 4 C. A secondary antibody was then applied and incubated at room temperature for two hours. Leukocyte recruitment into the tissue was evaluated with anti-CD45 antibody staining (1:100, SC-70690, mouse anti-rabbit, Santa Cruz, Dallas, TX, USA) and donkey anti-mouse secondary antibody (1:200, ab150110, Abcam, Waltham, MA, USA). Residual human IgG in the DDS and in the ocular tissues was determined using goat anti-human IgG secondary antibodyAF546 (1:200, A-21089, Thermo Scientific, Waltham, MA, USA) after blocking with 1% BSA. The total number and area of cells expressing CD45 in corneal sections were determined using the “Analyze Particles” tool in ImageJ 1.50e software, as previously described

[0018] . The mean ± standard deviation (SD) of different rabbits was reported. Statistical Analysis All experiments were performed with at least 3 technical replicates. Quantitative results were presented as means ± standard deviations. The normality of data was assessed by the Shapiro–Wilk test. One-way and two-way ANOVA tests were performed when data contained multiple variables and were corrected with Attorney Docket No.: 00633-0387WO1

[0013] Tukey’s. In addition to parametric tests, we confirmed results by using a non- parametric Mann–Whitney (t-test) and Kruskal– Wallis (ANOVA) tests. A mixed ANOVA was performed when data contained dependent variables (e.g., CNV and corneal defect area). The fixed variables were the time and treatment. Analyses were performed using the Statistical Package of Social Sciences (SPSS, IBM, Armonk, NY, USA), R Studio (Boston, MA, USA), and GraphPad Prism software Version 17 (San Diego, CA, USA). Linear and second-order polynomial functions were generated in GraphPad Prism Version 6.0 (GraphPad, La Jolla, CA, USA). Example 1. DDS Sol–Gel Transition and Drug Release Assessment In Vitro Using Fluorescein-Conjugated Dextran The PLGA-PEG-PLGA triblock copolymer used in this study presented a sol- gel transition at ~37 ℃ (FIGS.1A, B, D) within a few minutes. Cured 20% triblock hydrogel remains a transparent viscus at 37 ℃. This sol–gel transition temperature is below a rabbit’s body temperature (~38 ℃), thus allowing for the rapid formation of hydrogel-based drug reservoir upon injection, providing localized, long-term sustained release in the injection site. The 20% triblock hydrogel exhibited high water content, low stiffness, and plasticity, which can be particularly beneficial for ocular applications. Example 2. Long-Term Sustained Release of Antibodies into the Eye after Single Subconjunctival Injection of the DDS The ability to deliver anti-VEGF / anti-TNF-α inhibitors, as well as the safety and efficacy of the thermosensitive triblock polymer, was evaluated in vivo, following a single subconjunctival injection of the DDS in rabbit eyes with corneal alkali injuries. The DDS was injected as a cold liquid polymer in the superior bulbar subconjunctival 15 minutes after the corneal alkali burn, using a 30G needle and a 1 mL syringe. Upon injection, the polymer rapidly gelated (FIG. 2A) and formed a visible drug reservoir. The DDS biodegraded over the 3 months of follow-up (FIGS. 2B–G). Antibody penetration in the eye was evaluated via an aqueous humor sampling and analysis of the IgG content, using a human IgG ELISA kit (RAB0001, Sigma, Saint Louis, MO, USA). Upon DDS injection, the human IgG content in the aqueous humor of eyes injected either with therapeutic antibodies (Abs) or IgG (isotype control) exhibited a rapid Attorney Docket No.: 00633-0387WO1 increase for the first two weeks after injection (FIG.2H), followed by a gradual decrease between weeks 2 and 6 and subsequent normalization between weeks 6 and 12 (FIG. 2H). Immunofluorescent staining of human IgG in cryosectioned eyelid tissues showed that, 3 months after injection of the DDS, a substantial amount of human IgG was present in the bulbar and forniceal subconjunctival connective tissue, iris, ciliary body, and retina (FIGS. 2I–L). Histopathological examination 3 months after injection revealed normal-appearing ocular adnexa (FIG.2M). The immunohistochemical evaluation of human IgG presence in the retina of the contralateral uninjected eye of animals treated with IgG DDS showed an absence of human IgG (FIG. 2N). Example 3. Anti-TNF-α / Anti-VEGF DDS Treatment Completely Suppresses Corneal Angiogenesis after Injury A central corneal alkali burn in rabbit eyes led to progressive corneal NV in the superior and inferior corneal regions of IgG-DDS-treated eyes (FIG.3A). Corneal NV reached its peak at 1.5 months post injury (25% of superior cornea; 30% of inferior cornea) (FIGS.3A–D). In comparison, anti-VEGF DDS treatment led to the partial suppression of NV at 3 months, especially in the inferior cornea (maximal inferior NV: 30% with IgG vs.8% with anti-VEGF; * p < 0.05; Mixed ANOVA test with Tukey’s correction) but did not completely halt progression, as the area of NV continued to grow in all rabbits during the 3 months of follow-up (FIGS.3A–D). Moreover, the anti-VEGF DDS treatment showed marginal inhibition of superior corneal NV, as compared to the IgG control group (p > 0.05; mixed ANOVA test with Tukey’s correction). In contrast, anti-TNF-α / anti-VEGF DDS treatment led to the complete inhibition of NV in the superior and inferior cornea for 3 months, as compared to the IgG DDS treatment group (* p < 0.05; *** p < 0.001; mixed ANOVA test with Tukey’s correction; FIGS.3A–D). Example 4. Anti-TNF-α / Anti-VEGF DDS Treatment Improves Corneal Epithelial Healing after Injury IgG-DDS-treated eyes had persistent epithelial defects even at 1 month after injury (10% of cornea area), which gradually reduced in subsequent months Attorney Docket No.: 00633-0387WO1

[0014] (FIGS.4A–C). In eyes treated with anti-VEGF DDS, persistent epithelial defects peaked 2 months after injury (15% of cornea area), without resolution throughout the 3 months (FIGS.4A–C). In contrast, combined anti-TNF-α / anti-VEGF DDS treatment led to reduced corneal epithelial defects (2% of cornea area) at 1 month and complete corneal re-epithelialization at 2 months, with a stably intact epithelium when measured at 3 months (FIGS.4A–C). Quantification of the area of epithelial defect confirmed the effect of combination anti-TNF-α / anti-VEGF DDS as compared to the other two treatments (FIG.4C; * p < 0.05, mixed ANOVA test with Tukey’s multiple comparison test). As shown by the immunofluorescent staining of rabbit corneas, combined anti-TNF- α / anti-VEGF DDS treatment significantly reduced CD45+immune cell infiltration into the injured cornea (FIGS. 5C, D), as compared to IgG DDS (FIGS. 5A, D) or anti-VEGF DDS treatment (FIGS.5B, D; * p < 0.05, one-way ANOVA test with Tukey’s multiple comparison test). Example 5. Anti-TNF-α / Anti-VEGF DDS Treatment Prevents Retinal and Optic Nerve Damage after Injury It was shown that corneal alkali injury is associated with secondary retinal and optic nerve degeneration in mice, rabbits, and humans

[0026] and that, at least in experimental models, this damage is mediated by secondary inflammation independently of the intraocular pressure

[0026] . In alkali-injured eyes, combined anti- TNF-α / anti-VEGF DDS treatment significantly reduced post-injury retinal ganglion cell loss at 3 months, as compared to the IgG DDS treatment (2.7% RGC loss vs.45% RGC loss, respectively; p < 0.01; FIGS.6A–D). RGC loss was similar between the anti-VEGF- and IgG-DDS-treated groups (63% RGC loss vs.45% RGC loss, respectively; p > 0.05. FIGS.6B–D). Combined anti-TNF-α / anti-VEGF DDS treatment also significantly reduced peripheral and central optic nerve axon loss, as compared to IgG and anti-VEGF DDS treatments (FIGS.6K and 6L) (* p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001; mixed ANOVA test with Tukey’s correction). Example 6. Bi-specific antibody against VEGF and TNF- α To develop a bi-specific antibody targeting VEGF and TNF- α (FIG.7), a plasmid was designed to produce the bi-specific antibody in vivo. The expression Attorney Docket No.: 00633-0387WO1 plasmid contains CMV enhancer and promoter followed by antibody expression cassette (FIGS.12A-12D). The antibody cassette comprised a promoter (e.g., a CMV promoter), a signal peptide, an anti-TNF-α heavy chain, a linker, an anti-VEGF light chain, a linker, an anti-VEGF heavy chain, IRES, a signal peptide, and an anti-TNF-α light chain. The plasmid also comprised an origin of replication, ampicillin resistance gene, PolyA tail, enhancer, lac and SV40 promoter. The new antibody is based on a Fab-scFv-Fc architecture and contains sequences of bevacizumab for VEGF inhibition and adalimumab for TNF alpha inhibition (FIGS.8A-8B and FIGS.9A-9B). The bi-specific antibody can also be based on other formats known in the art. For example, the bi-specific antibody can be based on an scFvTNF-α – scFvVEGF format, a Fab-Ds-scFv format, or a CrossMAbVH-VLformat. Table C provides other combination of sequences that would work against VEGF and TNF-α. The bi-specific antibody was produced using human HEK293F cell line. Human cells were used to assess the biologic function of the novel bi-specific antibody, according to the benchmarks used described elsewhere

[0047] . To this end, the neutralizing efficacy of the anti-TNF alpha and anti-VEGF regions of the bi-specific antibody were equal to that of the adalimumab and bevacizumab, respectively, for the same molarity (FIGS.9 and 10). Example 7. Knob-in-hole bi-specific antibody A knob-in-hole bi-specific antibody was produced using knob-in-hole mutation with the same Fab-scFv-Fc format as described above. In the TNFα heavy chain, a M428L / N434S mutation was introduced to extend the half-life and L234A / L235A / P329A mutation was introduced to decrease the immunogenicity. In addition to the mutations introduced in the heavy chain of TNFα, a C220A disulfide bridge was introduced in the VEGF arm. The bi-specific antibody is bivalent and thus, comprises one binding site for each antigen. The antibody was concentrated in a custom buffer containing L-histidine (155 mcg), L-methionine (52.2 mcg), polysorbate 20 (20 mcg), sodium chloride (73.1 mcg), D-sucrose (2.74 mg) and water for injection, and pH was adjusted to 5.5 with acetic acid. Other buffers that can be used for reconstituting or concentrating the antibody can include: Attorney Docket No.: 00633-0387WO1

[0015] 1) Polysorbate 20 (0.015 mg), sodium chloride (0.117 mg), sodium phosphate monobasic monohydrate (0.055 mg), sodium phosphate dibasic heptahydrate (0.027 mg), sucrose (2.5 mg) and water for injection with a pH of 6.2; 2) 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80 and water for injection, USP. Sodium hydroxide was added as necessary to adjust the pH; or 3) α, α-trehalose dihydrate, polysorbate 20, sodium phosphate and water for injection. References 1. Bachmann, B.O.; Bock, F.; Wiegand, S.J.; Maruyama, K.; Dana, M.R.; Kruse, F.E.; Luetjen-Drecoll, E.; Cursiefen, C. Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch. Ophthalmol.2008, 126, 71–77. [CrossRef] 2. Vlasov, A.; Ryan, D.S.; Ludlow, S.; Coggin, A.; Weichel, E.D.; Stutzman, R.D.; Bower, K.S.; Colyer, M.H. Corneal and Corneoscleral Injury in Combat Ocular Trauma from Operations Iraqi Free-dom and Enduring Freedom. Mil. Med. 2017, 182, 114–119. [CrossRef] [PubMed] 3. Cardillo, J.A.; Stout, J.T.; LaBree, L.; Azen, S.P.; Omphroy, L.; Cui, J.Z.; Kimura, H.; Hinton, D.R.; Ryan, S.J. Post-traumatic proliferative vitreoretinopathy. The epidemiologic profile, onset, risk factors, and visual outcome. Ophthalmology 1997, 104, 1166–1173. [CrossRef] [PubMed] 4. Cade, F.; Grosskreutz, C.L.; Tauber, A.; Dohlman, C.H. Glaucoma in eyes with severe chemical burn, before and after keratopros- thesis. Cornea 2011, 30, 1322–1327. [CrossRef] [PubMed] 5. Dohlman, C.H.; Cade, F.; Regatieri, C.V.; Zhou, C.; Lei, F.; Crnej, A.; Harissi- Dagher, M.; Robert, M.-C.; Papaliodis, G.N.; Chen, D.; et al. Chemical Burns of the Eye: The Role of Retinal Injury and New Therapeutic Possibilities. Cornea 2018, 37, 248–251. [CrossRef] [PubMed] 6. Crnej, A.; Paschalis, E.I.; Salvador-Culla, B.; Tauber, A.; Drnovsek-Olup, B.; Shen, L.Q.; Dohlman, C.H. Glaucoma progression and role of glaucoma surgery in patients with Boston keratoprosthesis. Cornea 2014, 33, 349–354. [CrossRef] Attorney Docket No.: 00633-0387WO1

[0016] 7. Cade, F.; Paschalis, E.I.; Regatieri, C.V.; Vavvas, D.G.; Dana, R.; Dohlman, C.H. Alkali burn to the eye: Protection using TNF-alpha inhibition. Cornea 2014, 33, 382–389. [CrossRef] 8. Paschalis, E.I.; Lei, F.; Zhou, C.; Kapoulea, V.; Dana, R.; Chodosh, J.; Vavvas, D.G.; Dohlman, C.H. Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes. Proc. Natl. Acad. Sci. USA 2018, 115, E11359–E11368. [CrossRef] 9. Bock, F.; König, Y.; Dietrich, T.; Zimmermann, P.; Baier, M.; Cursiefen, C. Inhibition of angiogenesis in the anterior chamber of the eye. Ophthalmologe 2007, 104, 336–344. [CrossRef] 10. Manzano, R.P.; Peyman, G.A.; Khan, P.; Carvounis, P.E.; Kivilcim, M.; Ren, M.; Lake, J.C.; Chevez-Barrios, P. Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br. J. Ophthalmol.2007, 91, 804– 807. [CrossRef] 11. Habot-Wilner, Z.; Barequet, I.S.; Ivanir, Y.; Moisseiev, J.; Rosner, M. The inhibitory effect of different concentrations of topical bevacizumab on corneal neovascularization. Acta Ophthalmol. 2010, 88, 862–867. [CrossRef] 12. Bock, F.; Konig, Y.; Kruse, F.; Baier, M.; Cursiefen, C. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch. Clin. Exp. Ophthalmol. 2008, 246, 281–284. [CrossRef] 13. Kim, S.W.; Ha, B.J.; Kim, E.K.; Tchah, H.; Kim, T.I. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology 2008, 115, e33– e38. [CrossRef] 14. Dastjerdi, M.H.; Al-Arfaj, K.M.; Nallasamy, N.; Hamrah, P.; Jurkunas, U.V.; Pineda, R., 2nd; Pavan-Langston, D.; Dana, R. Topical bevacizumab in the treatment of corneal neovascularization: Results of a prospective, open-label, noncomparative study. Arch. Ophthalmol. 2009, 127, 381–389. [CrossRef] [PubMed] 15. Paschalis, E.I.; Lei, F.; Zhou, C.; Kapoulea, V.; Thanos, A.; Dana, R.; Vavvas, D.G.; Chodosh, J.; Dohlman, C.H. The Role of Microglia and Peripheral Monocytes in Retinal Damage after Corneal Chemical Injury. Am. J. Pathol. 2018, 188, 1580–1596. [CrossRef] [PubMed] Attorney Docket No.: 00633-0387WO1

[0017] 16. Arevalo, J.F.; Serrano, M.A.; Wu, L. Combined inhibition of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) for the treatment of macular edema of various etiologies: A short-term pilot study. Eye 2013, 27, 569–571. [CrossRef] [PubMed] 17. Freitas, L.G.A.d.; Isaac, D.L.C.; Tannure, W.T.; Gabriel, L.A.R.; Reis, R.G.d.; Rassi, A.R.; Freitas, C.A.d.; Ávila, M.P.d. Intravitreal bevacizumab combined with infliximab in the treatment of choroidal neovascularization secondary to age-related macular degeneration: Case report series. Arq. Bras. Oftalmol. 2013, 76, 180–184. [CrossRef] 18. Zhou, C.; Robert, M.C.; Kapoulea, V.; Lei, F.; Stagner, A.M.; Jakobiec, F.A.; Dohlman, C.H.; Paschalis, E.I. Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye. Investig. Ophthalmol. Vis. Sci.2017, 58, 96–105. [CrossRef] 19. Nomoto, H.; Shiraga, F.; Kuno, N.; Kimura, E.; Fujii, S.; Shinomiya, K.; Nugent, A.K.; Hirooka, K.; Baba, T. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Investig. Ophthalmol. Vis. Sci.2009, 50, 4807–4813. [CrossRef] 20. Stevenson, W.; Cheng, S.F.; Dastjerdi, M.H.; Ferrari, G.; Dana, R. Corneal neovascularization and the utility of topical VEGF inhibition: Ranibizumab (Lucentis) vs bevacizumab (Avastin). Ocul. Surf. 2012, 10, 67–83. [CrossRef] 21. Chang, J.H.; Garg, N.K.; Lunde, E.; Han, K.Y.; Jain, S.; Azar, D.T. Corneal neovascularization: An anti-VEGF therapy review. Surv. Ophthalmol.2012, 57, 415–429. [CrossRef] 22. Ranta, V.P.; Mannermaa, E.; Lummepuro, K.; Subrizi, A.; Laukkanen, A.; Antopolsky, M.; Murtomaki, L.; Hornof, M.; Urtti, A. Barrier analysis of periocular drug delivery to the posterior segment. J. Control Release 2010, 148, 42–48. [CrossRef] [PubMed] 23. Del Amo, E.M.; Rimpela, A.K.; Heikkinen, E.; Kari, O.K.; Ramsay, E.; Lajunen, T.; Schmitt, M.; Pelkonen, L.; Bhattacharya, M.; Richardson, D.; et al. Pharmacokinetic aspects of retinal drug delivery. Prog. Retin. Eye Res. 2017, 57, 134–185. [CrossRef] [PubMed] Attorney Docket No.: 00633-0387WO1

[0018] 24. Tong, X.; Pan, W.; Su, T.; Zhang, M.; Dong, W.; Qi, X. Recent advances in natural polymer-based drug delivery systems. React. Funct. Polym. 2020, 148, 104501. [CrossRef] 25. Garner, J. Users Guide for Thermogelling PolyVivo PLGA-PEG-PLGA (AK12 / AK19 / AK24). Available online: https: / / akinainc. com / pdf / 40307- PolyVivo-thermogel-usersguide.pdf (accessed on 28 August 2021). 26. Paschalis, E.I.; Zhou, C.; Lei, F.; Scott, N.; Kapoulea, V.; Robert, M.-C.; Vavvas, D.; Dana, R.; Chodosh, J.; Dohlman, C.H. Mechanisms of Retinal Damage after Ocular Alkali Burns. Am. J. Pathol. 2017, 187, 1327–1342. [CrossRef] 27. Paschalis, E.I.; Lei, F.; Zhou, C.; Chen, X.N.; Kapoulea, V.; Hui, P.-C.; Dana, R.; Chodosh, J.; Vavvas, D.G.; Dohlman, C.H. Microglia Regulate Neuroglia Remodeling in Various Ocular and Retinal Injuries. J. Immunol.2019, 202, 539– 549. [CrossRef] [PubMed] 28. Chen, X.; Lei, F.; Zhou, C.; Chodosh, J.; Wang, L.; Huang, Y.; Dohlman, C.H.; Paschalis, E.I. Glaucoma after ocular surgery or trauma: The role of infiltrating monocytes and their response to cytokine inhibitors. Am. J. Pathol.2020, 190, 2056–2066. [CrossRef] 29. Zhou, C.; Singh, A.; Qian, G.; Wolkow, N.; Dohlman, C.H.; Vavvas, D.G.; Chodosh, J.; Paschalis, E.I. Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye. Transl. Vis. Sci. Technol.2020, 9, 5. [CrossRef] 30. Englander, M.; Chen, T.C.; Paschalis, E.I.; Miller, J.W.; Kim, I.K. Intravitreal injections at the Massachusetts Eye and Ear Infirmary: Analysis of treatment indications and postinjection endophthalmitis rates. Br. J. Ophthalmol.2013, 97, 460–465. [CrossRef] 31. Robert, M.-C.; Frenette, M.; Zhou, C.; Yan, Y.; Chodosh, J.; Jakobiec, F.A.; Stagner, A.M.; Vavvas, D.; Dohlman, C.H.; Paschalis, E.I. A Drug Delivery System for Administration of Anti-TNF-α Antibody. Transl. Vis. Sci. Technol. 2016, 5, 11. [CrossRef] 32. Dohlman, C.H.; Zhou, C.; Lei, F.; Cade, F.; Regatieri, C.V.; Crnej, A.; Dohlman, J.G.; Shen, L.Q.; Paschalis, E.I. Glaucoma After Corneal Trauma or Surgery—A Rapid, Inflammatory, IOP-Independent Pathway. Cornea 2019, 38, 1589. [CrossRef] Attorney Docket No.: 00633-0387WO1

[0019] 33. Xie, B.; Jin, L.; Luo, Z.; Yu, J.; Shi, S.; Zhang, Z.; Shen, M.; Chen, H.; Li, X.; Song, Z. An injectable thermosensitive polymeric hydrogel for sustained release of Avastin®to treat posterior segment disease. Int. J. Pharm. 2015, 490, 375–383. [CrossRef] [PubMed] 34. Koenig, Y.; Bock, F.; Horn, F.; Kruse, F.; Straub, K.; Cursiefen, C. Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch. Clin. Exp. Ophthalmol. 2009, 247, 1375–1382. [CrossRef] [PubMed] 35. Lin, C.-T.; Hu, F.-R.; Kuo, K.-T.; Chen, Y.-M.; Chu, H.-S.; Lin, Y.-H.; Chen, W.-L. The Different Effects of Early and Late Bevacizumab (Avastin) Injection on Inhibiting Corneal Neovascularization and Conjunctivalization in Rabbit Limbal Insufficiency. Investig. Ophthalmol. Vis. Sci.2010, 51, 6277–6285. [CrossRef] [PubMed] 36. Canete, J.D.; Pablos, J.L.; Sanmarti, R.; Mallofre, C.; Marsal, S.; Maymo, J.; Gratacos, J.; Mezquita, J.; Mezquita, C.; Cid, M.C. Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis. Arthritis Rheum.2004, 50, 1636–1641. [CrossRef] 37. Appel, H.; Janssen, L.; Listing, J.; Heydrich, R.; Rudwaleit, M.; Sieper, J. Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment. Arthritis Res. Ther.2008, 10, R125. [CrossRef] 38. Klimiuk, P.A.; Sierakowski, S.; Domyslawska, I.; Chwiecko, J. Effect of etanercept on serum levels of soluble cell adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor in patients with rheumatoid arthritis. Scand. J. Rheumatol.2009, 38, 439–444. [CrossRef] 39. Murdaca, G.; Spanò, F.; Miglino, M.; Puppo, F. Effects of TNF-α inhibitors upon the mechanisms of action of VEGF. Immunotherapy 2013, 5, 113–115. [CrossRef] 40. Ferrari, G.; Bignami, F.; Rama, P. Tumor Necrosis Factor-α Inhibitors as a Treatment of Corneal Hemangiogenesis and Lymphan- giogenesis. Eye Contact Lens Sci. Clin. Pract.2014, 41, 72–76. [CrossRef] Attorney Docket No.: 00633-0387WO1

[0020] 41. Wang, H.; Han, X.; Wittchen, E.S.; Hartnett, M.E. TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS- dependent β-catenin activation. Mol. Vis.2016, 22, 116–128. 42. Paschalis, E.I.; Robert, M.-C.; Dohlman, C.H. Treatment of Chemical Burn to the Eye: A Changing Picture; Springer: Cham, Switzerland, 2018; pp.1–24. 43. Dohlman, C.H.; Robert, M.-C.; Paschalis, E.I. Treatment of Chemical Burn to the Eye: A Changing Picture. In Foundations of Corneal Disease: Past, Present and Future; Colby, K., Dana, R., Eds.; Springer International Publishing: Cham, Switzerland, 2020; pp.109–119. 44. Rezaeian Shiadeh, S.N.; Hadizadeh, F.; Khodaverdi, E.; Gorji Valokola, M.; Rakhshani, S.; Kamali, H.; Nokhodchi, A. Injectable In-Situ Forming Depot Based on PLGA and PLGA-PEG-PLGA for Sustained-Release of Risperidone: In Vitro Evaluation and Pharmacokinetics in Rabbits. Pharmaceutics 2023, 13, 1229. [CrossRef] [PubMed] 45. C. A. Curcio, N. E. Medeiros, C. L. Millican, Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 37, 1236-1249 (1996). 46. C. Zhou, et al., Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma. Pharmaceutics 15, 2059 (2023). 47. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D'Amore PA, Miller JW. Inhibition of vascular endothelial growth factor prevents retinal ischemia—associated iris neovascularization in a nonhuman primate. Archives of ophthalmology.1996 Jan 1;114(1):66-71 OTHER EMBODIMENTS It is to be understood that while the disclosure 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.

Claims

Attorney Docket No.: 00633-0387WO1WHAT IS CLAIMED IS:

1. A bi-specific antibody molecule comprising: (a) a first antigen binding domain binds to VEGF; and (b) a second antigen binding domain that binds to TNF-α, wherein the first antigen binding domain and the second antigen binding domains are linked together by a linker; and can be in any order.

2. The bi-specific antibody of claim 1, wherein the first antigen binding domain comprises a light chain variable region (LC) comprising a sequence that is at least 90% identical to a LC amino acid sequence set forth in Tables A, D, E, and H to P, and a heavy chain variable region (HC) comprising a sequence that is at least 90% identical to a HC amino acid sequence set forth in Tables A, D, E, and H to P.

3. The bi-specific antibody of claim 1, wherein the second antigen binding domain comprises a LC comprising a sequence that is at least 90% identical to a LC amino acid sequence set forth in Tables B, D, E, and H to P, and a HC comprising a sequence that is at least 90% identical to a HC amino acid sequence set forth in Tables B, D, E, and H to P.

4. The bi-specific antibody molecule of any one of claims 1-3, comprising a combination of antibody or antigen binding domain thereof set forth in Tables C, D, E, and H to P.

5. The bi-specific antibody molecule of any one of claims 1-4, optionally wherein the Fc is engineered to extend half-life and / or to silence antibody- dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), preferably comprising amino acid sequences set forth in Tables D, E, and H to P.

6. A pharmaceutical composition comprising the bi-specific antibody molecule of any one of claims 1-5 and a pharmaceutically acceptable carrier.Attorney Docket No.: 00633-0387WO1 7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier is a slow-release polymer.

8. The pharmaceutical composition of claim 7, wherein the slow-release polymer is PLGA-PEG-PLGA triblock polymer, Poly(lactic-co-glycolic acid) (PLGA), Polyethylene glycol (PEG), Poly(ethylene oxide) (PEO), Poly(ethyleneimine) (PEI), Poly(l-lysine) (PLL), Poly(caprolactone) (PCL), Poly(vinyl alcohol) (PVA), Chitosan, Hyaluronic acid (HA), Poly(β-amino esters) (PBAEs), Poly(N-isopropylacrylamide) (PNIPAM), Poly(alkyl cyanoacrylates) (PACA), Poly(propylene sulfide) (PPS), Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO or Pluronics), Poly(beta- amino esters) (PBAEs), Poly(ortho esters) (POEs), Poly(glycolic acid) (PGA), Poly(hydroxyethyl methacrylate) (PHEMA), or Poly(2-oxazoline) (POx), Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO- PPO-PEO or Pluronic).

9. A method for treating ocular neovascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a VEGF inhibitor and a TNF-α inhibitor.

10. A method for treating ocular neovascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a bi-specific antibody molecule of any of claims 1 to 8 that targets both VEGF and TNF-α.

11. The method of claims 9 or 10, wherein the subject is a mammal.

12. The method of claims 9 or 10, wherein the subject has wet age-related macular degeneration, retinopathy, proliferative vitreoretinopathy, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, central serous chorioretinopathy, myopic macular degeneration, Coats' disease, choroidalAttorney Docket No.: 00633-0387WO1 neovascularization, Posterior uveitis - Vogt-Koyanagi-Harada syndrome, uveitis, histoplasmosis-related choroiditis - ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, peripheral retinal neovascularization - sickle cell retinopathy / Eales' disease, ocular trauma, corneal neovascularization, iris neovascularization - rubeosis iridis, ocular tumors, microangiopathy, neovascular glaucoma, corneal graft rejection, glaucoma, herpetic and infectious keratitis, ocular ischemia, neovascular glaucoma, corneal, uveal and iris neovascularization, conjunctivalization, stromal scaring, orbital and eyelid tumors, pterygium, Stevens Johnson Syndrome, ocular cicatricial pemphigoid, intraocular complications, ocular wounds or other ocular injuries, and ocular surface diseases.

13. The method of claim 12, wherein the ocular injury comprises: (a) a chemical injury due to exposure to irritants, acids, or bases; or (b) a surgical injury due to penetrating keratoplasty, keratoprosthesis surgery, glaucoma drainage device implantation or glaucoma bypass stent.

14. The method of claim 12, wherein the retinopathy is selected from the group consisting of retinopathy of prematurity (ROP); diabetic retinopathy; retinal vein occlusion; sickle cell retinopathy; Stargardt's disease; choroidal neovascularization; and radiation retinopathy.

15. The method of claim 12, wherein the intraocular complication is a peripheral anterior synechiae, a proliferative vitreoretinopathy, an iatrogenic including ocular surgery or cyclophotocoagulation.

16. The method of claim 9, wherein the VEGF inhibitor is selected from the group consisting of bevacizumab; ranibizumab; aflibercept; and brolucizumzb.

17. The method of claim 9, wherein the TNF-α inhibitor selected from the group consisting of etanercept; infliximab; adalimumab; certolizumab pegol; and golimumab.Attorney Docket No.: 00633-0387WO118. The method of claims 9 or 10, wherein administering is topical administration onto the eye.

19. The method of claims 9 or 10, wherein administering is injecting at, into, or near the superior / inferior / nasal / temporal bulbar subconjunctival, intracorneal, intrastromal, intravitreal, intralimbal, subretinal, intraretinal, intralenticular, intrascleral, transscleral, suprachoroidal, intracameral, sub-bulbar, subtenon, orbit, or eyelid.

20. The method of any one of claims 9-19, wherein the treatment results in reduced or delayed ocular neovascularization.

21. One or more nucleic acids encoding the bi-specific antibody of any one of claims 1 to 10.

22. A vector comprising nucleic acids of claim 21.

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