Methods for treatment of diabetic macular edema with an Anti-tie2 antibody conjugate

Abstract

The present disclosure provides methods and compositions for treating diabetic macular edema (DME) with an anti-tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (Tie2) antibody conjugate.

Description

[0001] Attorney Docket No.: 146392070440

[0002] METHODS FOR TREATMENT OF DIABETIC MACULAR EDEMA WITH AN ANTI-TIE2 ANTIBODY CONJUGATE

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of United States Provisional Patent Application No. 63 / 746,541 filed January 17, 2025, United States Provisional Patent Application No. 63 / 791,027 filed April 18, 2025, and United States Provisional Patent Application No. 63 / 892,387 filed October 2, 2025. The contents of those applications are hereby incorporated by reference herein in their entirety.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] The contents of the electronic sequence listing (146392070440SEQLIST.xml; Size: 25,848 bytes; and Date of Creation: January 15, 2026) is herein incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] The present invention relates to the treatment of diabetic macular edema (DME) with an anti-tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (Tie2) antibody conjugate.

[0008] BACKGROUND OF THE INVENTION DME, a complication of diabetic retinopathy (DR), can develop at any stage of the underlying disease of retinal micro vasculature (Fong et al., Diabetes Care, 27:2540-53, 2004). DME occurs with increasing frequency as the underlying DR worsens (Henricsson et al., Acta Ophthalmol Scand, 77:218-23, 1999; Johnson, Am J Ophthalmol 147:11-21, 2009) from non-proliferative DR to proliferative DR (PDR). As a result of the breakdown of the blood-retinal barrier, fluid and serum macromolecules leak into the interstitial spaces of the surrounding retina. The resulting accumulation of fluid within the macular area causes DME, which is the most common cause of moderate and severe visual impairment in patients with DR

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[0010] MF-366104678Attorney Docket No.: 146392070440

[0011] (Ciulla et al., Diabetes Care, 26:2653-64, 2003; Leasher et al., Diabetes Care 39:164309, 2016). If left untreated, DME can lead to a loss of 10 or more letters in visual acuity (VA) within 2 years in approximately 50% of patients (Ferris and Patz, Surv Ophthamol, 28 Suppl:452-61, 1984; Ciulla et al., Diabetes Care, 26:2653-64, 2003). The global diabetes prevalence in 2019 was 9.3% (463 million people) and is estimated to rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045 (Saeedi et al., Diabetes Res Clin Pract, 157:107843, 2019). Considering that DME affects approximately 14% of patients with diabetes mellitus (DM) and can be found in both Type 1 and Type 2 DM patients (Girach and Lund- Andersen, Int J Clin Practice, 61:88-97, 2007), the prevalence of DME is also expected to significantly rise due to the increasing numbers of DM throughout the world.

[0012] Although macular laser used to be the standard of care for treatment of DME, the development of anti-vascular endothelial growth factor (anti-VEGF) pharmacotherapy in the past two decades has led to dramatic improvements in visual outcomes for patients with DME. Currently available anti-VEGF therapies for DME include ranibizumab, brolucizumab, aflibercept, and anti-VEGF / anti-angiopoietin-2 (Ang-2) therapy, faricimab.

[0013] Despite the efficacy achieved with anti-VEGF therapies in DME, a significant percentage of patients do not achieve optimal functional vision (e.g., vision required to obtain a driver’s license), suggesting that anti-VEGF treatment does not address all the pathways underlying DME pathology. New treatments with improved clinical efficacy and reduced treatment burden are needed to address the high, unmet medical need in DME.

[0014] On a molecular level, DME is a result of a VEGF-A-mediated increase in vessel permeability and loss of pericytes, consequent to hypoxia-mediated release of pro angiogenic, hyperpermeability, and pro inflammatory mediators. VEGF also upregulates a homeostatic factor, Ang-2, which acts as a competitive antagonist of the Tie2 receptor tyrosine kinase on endothelial cells, counteracting vessel stabilization maintained through angiopoietin- 1 (Ang-l)-dependent Tie2 activation.

[0015] 2

[0016] MF-366104678Attorney Docket No.: 146392070440

[0017] Tie2 activation triggers several cellular and junctional changes, leading to improved vascular stability and reduced vascular permeability. To activate Tie2, one potential approach is to block the antagonist ligand Ang-2. However, the efficacy of an Ang-2 inhibitor relies on the presence of adequate level of endogenous Ang-1, which may not always be the case. Ang-1 exists in highly oligomerized forms, and ligand-mediated clustering of Tie2 is a cardinal feature of Tie2 activation. RO7446603 is a multivalent molecule designed to directly promote Tie2 clustering and activation. Therefore, Tie2 activation by RO7446603 is independent of the presence of endogenous Ang- 1.

[0018] There is an unmet need for methods of treating DME with therapies that act independently of endogenous Ang-1.

[0019] SUMMARY OF THE INVENTION

[0020] In one aspect, the disclosure provides a method of treating diabetic macular edema (DME) in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.05 mg per eye of a conjugate that binds tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (Tie2), wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

[0021] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to

[0022] 3

[0023] MF-366104678Attorney Docket No.: 146392070440

[0024] the human patient one or more fixed dose(s) of 0.05 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0025] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every two months).

[0026] In some aspects, the method comprises, prior to intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every four weeks for the first six doses.

[0027] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

[0028] In some aspects, a fixed dose of 0.05 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

[0029] In some aspects, a fixed dose of 0.05 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for four doses.

[0030] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.1 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence

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[0032] MF-366104678Attorney Docket No.: 146392070440

[0033] RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0034] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.1 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0035] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every two months).

[0036] In some aspects, the method comprises, prior to intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every four weeks for the first six doses.

[0037] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

[0038] In some aspects, a fixed dose of 0.1 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

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[0040] MF-366104678Attorney Docket No.: 146392070440

[0041] In some aspects, a fixed dose of 0.1 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for four doses.

[0042] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.15 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0043] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.15 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0044] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every two months).

[0045] In some aspects, the method comprises, prior to intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every four weeks for the first six doses.

[0046] 6

[0047] MF-366104678Attorney Docket No.: 146392070440

[0048] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

[0049] In some aspects, a fixed dose of 0.15 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

[0050] In some aspects, a fixed dose of 0.15 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for four doses.

[0051] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.4 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0052] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.4 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0053] 7

[0054] MF-366104678Attorney Docket No.: 146392070440

[0055] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every two months).

[0056] In some aspects, the method comprises, prior to intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every four weeks for the first six doses.

[0057] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

[0058] In some aspects, a fixed dose of 0.4 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

[0059] In some aspects, a fixed dose of 0.4 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for four doses.

[0060] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 1.3 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0061] 8

[0062] MF-366104678Attorney Docket No.: 146392070440

[0063] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 1.3 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0064] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every two months).

[0065] In some aspects, the method comprises, prior to intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every four weeks for the first six doses.

[0066] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

[0067] In some aspects, a fixed dose of 1.3 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

[0068] In some aspects, a fixed dose of 1.3 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for four doses.

[0069] In some aspects, each of the one or more fixed dose(s) of the conjugate are intravitreally co-administered with faricimab.

[0070] In some aspects, each of the one or more fixed dose(s) of the conjugate are intravitreally co-administered with 6 mg faricimab per eye.

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[0072] MF-366104678Attorney Docket No.: 146392070440

[0073] In some aspects, the co-administration comprises administration of the conjugate and the faricimab together or separately.

[0074] In some aspects, the conjugate and the faricimab are (a) co-mixed and administered as a single intravitreal (IVT) injection; or (b) administered as separate IVT injections.

[0075] In some aspects, (a) the VH of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7; or (b) the VL of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8.

[0076] In some aspects, the VH of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7 and the VL of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8.

[0077] In some aspects, (a) the VH of each of the six Fabs comprises the amino acid sequence of SEQ ID NO: 7; and (b) the VL of each of the six Fabs comprises the amino acid sequence of SEQ ID NO: 8.

[0078] In some aspects, each of the six Fabs comprises (a) a Fab heavy chain (HC) comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; (b) a Fab light chain (LC) comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10; or (c) a Fab HC comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9 and a Fab LC comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10.

[0079] In some aspects, each of the six Fabs comprises (a) a Fab HC comprising the amino acid sequence of SEQ ID NO: 9; (b) a Fab LC comprising the amino acid sequence of SEQ ID NO: 10; or (c) a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In a preferred aspect, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10.

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[0081] MF-366104678Attorney Docket No.: 146392070440

[0082] In some aspects, each of the six Fabs comprises a Fab HC and a Fab LC, and wherein each of the six Fabs is linked to a different arm of the hexameric PEG molecule through a free sulfhydryl group of a cysteine amino acid residue at: (a) position 120, 166, 178, 187, or 209 in the Fab HC; or (b) position 124, 142, 155, 201, 206, 107, 126, or 149 in the Fab LC, wherein the residue number is according to EU numbering.

[0083] In some aspects, each of the six Fabs is linked to a different arm of the hexameric PEG molecule through a free sulfhydryl group of a cysteine amino acid residue at position 209 in each Fab HC, wherein the residue number is according to EU numbering. In a preferred aspect, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. It is understood that for the Fab HC comprising the amino acid sequence of SEQ ID NO: 9, position 209 of the Fab HC according to EU numbering is synonymous with position 212 of the Fab HC according to linear, sequential numbering.

[0084] In some aspects, the hexameric PEG molecule has an average molecular weight of about 500 Daltons (Da) to about 300,000 Da.

[0085] In some aspects, the hexameric PEG molecule has a weight average molecular weight of about 500 Da to about 300,000 Da.

[0086] In some aspects, the hexameric PEG molecule has an average molecular weight of about 1000 Da to about 10,000 Da.

[0087] In some aspects, the hexameric PEG molecule has a weight average molecular weight of about 1000 Da to about 10,000 Da.

[0088] In some aspects, the hexameric PEG molecule has an average molecular weight (e.g., a weight average molecular weight) of about 5400 Da to about 6600 Da.

[0089] In some aspects, the hexameric PEG molecule has the structure of general formula lb:

[0090] 11

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[0092]

[0093] wherein each m is independently an integer from 3-250; each R1is independently either absent or is a linking group; and each R2is independently either hydrogen or a terminal reactive group; and wherein at least one R2is a terminal reactive group and is conjugated to one of the six Fabs. In some aspects, each R2is a maleimide.

[0094] In some aspects, the hexameric PEG molecule has the structure of general formula lb:

[0095] (CH; CH2O)niR{R2

[0096] 6

[0097] CH;

[0098] :”(0CH20H? XB~0 -■ CH; - C — CH2—O — CH; ~C — CHj “0 — (CHjCHjOJra 'R -R2

[0099] CH; CH;

[0100] C 6

[0101]

[0102] (CH; CH; O> TSR’R2(CHjCM jOirn R ’ R”

[0103] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure:

[0104] o

[0105] _ H II2

[0106] (CH2) — N-C— (CH2)— R2,u2•

[0107] , wherein i and j are 2, and wherein each R is a maleimide and is conjugated to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of the Fab HC of the Fab, wherein the residue number is according to EU numbering.

[0108] In some aspects, the hexameric PEG molecule has the structure of general formula lb:

[0109] 12

[0110] MF-366104678Attorney Docket No.: 146392070440

[0111] (CHJOHJQJWH’R2(CH; CH2O)mRV

[0112] O

[0113] 6

[0114] CH; CH;

[0115] R2Ri „ (OCH; CH;>rs — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C HjCHjOyft ' R:RZ

[0116] CH; CH;

[0117] Q o

[0118] (CH; CH jO R

[0119]

[0120] (CHjCH^^R'R2 {R’"

[0121] wherein each m is independently an integer from 3-250; each R1is independently either absent or is a linking group; and each R2is independently either hydrogen or a terminal reactive group; and wherein at least one R2is a terminal reactive group and is covalently linked to one of the six Fabs.

[0122] In some aspects, each R2is a terminal reactive group and is covalently linked to the Fab HC of each of the Fabs.

[0123] In some aspects, each R2is a maleimide and is covalently linked to the Fab HC of each of the Fabs.

[0124] In some aspects, the hexameric PEG molecule has the structure of general formula lb:

[0125] (CHjCHsOJmR’R2(C^CHJC^R’R2

[0126] y p

[0127] R2R1~ (GCH; CH2XB “O •~CH2~C~CH;~-O~~ CH2~~C~~CH;“O - (CHjCH; OkrrR'R?

[0128] OH? OH^

[0129]

[0130] o 6

[0131] (QH CH;:CJ)reR(R2(OH2CH;< W5R2

[0132] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure:

[0133] o

[0134] H II

[0135] § (CH2)— N-C— (CH2)— R2...2.

[0136] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of the Fab HC of the Fab, wherein the residue number is according to EU numbering.

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[0139] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising: (a) intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and (b) following (a), intravitreally administering a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0140] (CH2CH2O)aiR!R2

[0141] O CH; CH2

[0142] R? & 0H2"0"" CHJ™O™-CHZ ■ -C -■■■■ CHj - O ■ R:R2

[0143] Ci-b CH;

[0144] o 6

[0145]

[0146] (CHJCHJO^R’R2iCHjCHjOjmR’R2

[0147] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0148] o

[0149] H II

[0150] § (CH2) — N-C— (CH2)j— R2..2.

[0151] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0152] In another aspect, the disclosure provides method of treating DME in a human patient in need thereof, the method comprising: (a) intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and (b) following (a),

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[0154] MF-366104678Attorney Docket No.: 146392070440

[0155] intravitreally administering a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0156]

[0157] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0158] H II

[0159] - (CH2)i— N— C — (CH2)j— R2

[0160] , wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0161] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising: (a) intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and (b) following (a), intravitreally administering a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT

[0162] 15

[0163] MF-366104678Attorney Docket No.: 146392070440

[0164] injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0165] 'f

[0166] CH? GH?

[0167] R2R ' — -(OCHjCH?;m - O ™ CHj ~C — CHj — 0 — CH j — C — CH? —O — (CHjCHjOJm -R ' R2

[0168] CH? CH?

[0169] 5 =

[0170] O p

[0171]

[0172] (CHiCHjO)f BR ’ Ra(CH? CH? O)m H1R2

[0173] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0174] o

[0175] H II

[0176] § (CH2) — N-C— (CH2)j— R2..2.

[0177] , wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0178] In another aspect, the disclosure provides method of treating DME in a human patient in need thereof, the method comprising: (a) intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and (b) following (a), intravitreally administering a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six

[0179] 16

[0180] MF-366104678Attorney Docket No.: 146392070440

[0181] Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0182] f

[0183] fp R1— -(OCHjCH jjm ■■ O -■ CHj ~C. OHj. O. CH j. C — CH? -O. (CHjCHjD )m -R1ft2

[0184] CH? CHJ

[0185] O O

[0186]

[0187] ’ P? (CHjCMzUJrnHfR~

[0188] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0189] o

[0190] H II

[0191] (CH2) — N-C— (CH2)j— R2..2.

[0192] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0193] In another aspect, the disclosure provides a method of treating DME in a human patient in need thereof, the method comprising: (a) intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and (b) following (a), intravitreally administering a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0194] 17

[0195] MF-366104678Attorney Docket No.: 146392070440

[0196] (CHJCHJQJWR’R2

[0197] (GHjCHsOJmRW

[0198] o 6

[0199] CH; CH;

[0200] R2R5 „ (OCH; CH;>rs ~G — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C HjCHjOyft ' R:RZ

[0201] CH; CH;

[0202] i

[0203] O o

[0204] (CH; CH jO R{R’"

[0205]

[0206] (OHjCH^iwR'R2

[0207] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0208] o

[0209] _ H n

[0210] (CH2)i— N-C— (CH2)j— R2..2.

[0211] ', wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0212] In some aspects, the treatment results in an improvement from baseline in best-corrected visual acuity (BCVA).

[0213] In some aspects, the treatment results in an improvement from baseline in central subfield thickness (CST).

[0214] In another aspect, the disclosure provides a kit comprising a conjugate that binds Tie2 and a package insert comprising instructions for using the conjugate for treating DME in an individual in need thereof according to the method of any one of the preceding aspects. In some embodiments, the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.05 mg of the conjugate. In some embodiments, the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.1 mg of the conjugate. In some embodiments, the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.15 mg of the conjugate. In some embodiments, the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.4 mg of the conjugate. In some embodiments, the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 1.3

[0215] 18

[0216] MF-366104678Attorney Docket No.: 146392070440

[0217] mg of the conjugate. In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab. In some embodiments, the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule. In some embodiments, each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0218] < CH3CHJO> TSR1FF (CH2OtyO)-nS1R2

[0219] O 6

[0220] CHj

[0221] pi R- - ■■ o CHJ - a CH2o ay • O.0Hr-0. (CH20H2O)tn -R-}F

[0222] CH2CHj

[0223] Q Q

[0224]

[0225] iCHjCH jQJfnR1R2

[0226] wherein each m is independently an integer from 10-30,

[0227] wherein R1and R2when taken together has the structure

[0228] o

[0229] H H

[0230] (CH2)i— N-C — (CH2)j— R2

[0231] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at

[0232] 19

[0233] MF-366104678Attorney Docket No.: 146392070440

[0234] position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the kits further comprise a second container that contains one or more unit dose(s) of faricimab. In some embodiments, the second container contains a unit dose of 6 mg faricimab. In some embodiments, the instructions indicate that the conjugate is to be administered in combination with one or more unit dose(s) of faricimab, e.g., one or more unit dose(s) of 6 mg faricimab per eye.

[0235] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,

[0236] wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0237] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0238] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s)

[0239] 20

[0240] MF-366104678Attorney Docket No.: 146392070440

[0241] of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0242] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0243] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,

[0244] wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino

[0245] 21

[0246] MF-366104678Attorney Docket No.: 146392070440

[0247] acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0248] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0249] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,

[0250] wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0251] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0252] 22

[0253] MF-366104678Attorney Docket No.: 146392070440

[0254] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,

[0255] wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0256] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0257] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence

[0258] 23

[0259] MF-366104678Attorney Docket No.: 146392070440

[0260] of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0261] (CHjCH? O)nsR1R2(CH> CH2O)-nRV

[0262] o 6

[0263] CH, CH?

[0264] R:;R5— (OCHjCH; - O — CHj ~ C ~~ CHS ™O — Ci- CH; du?

[0265] o o

[0266]

[0267] iOH;; CH?OWN2

[0268] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0269] o

[0270] L § _ H

[0271]

[0272] (CH^-N-C n- ~(CH2) ~ R2..2.

[0273] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0274] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0275] 24

[0276] MF-366104678Attorney Docket No.: 146392070440

[0277] (CHJCHJQJWR’R2

[0278] (GHjCHsOJmRW

[0279] o 6

[0280] CH;

[0281] R2R5 „ (OCH; CH;>rs ~G — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C H; CH2O)*>; ' R:RZ

[0282] CH; CH;

[0283] i

[0284] O o

[0285] (CH; CH jO R

[0286]

[0287] (OHjCH^iwR'R2 {R’"

[0288] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0289] o

[0290] _ H n

[0291] (CH2)i— N-C— (CH2)j— R2..2.

[0292] ', wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0293] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0294] 25

[0295] MF-366104678Attorney Docket No.: 146392070440

[0296] (CHJCHJQJWR’R2

[0297] (GHjCHsOJmRW

[0298] o 6

[0299] CH;

[0300] R2R5 „ (OCH; CH;>rs ~G — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C H; CH2O)*>; ' R:RZ

[0301] CH; CH;

[0302] i

[0303] O o

[0304] (CH; CH jO R

[0305]

[0306] (OHjCH^iwR'R2 {R’"

[0307] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0308] o

[0309] _ H n

[0310] (CH2)i— N-C— (CH2)j— R2..2.

[0311] ', wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0312] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0313] 26

[0314] MF-366104678Attorney Docket No.: 146392070440

[0315] (CHJCHJQJWR’R2

[0316] (GHjCHsOJmRW

[0317] o 6

[0318] CH;

[0319] R2R5 „ (OCH; CH;>rs ~G — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C H; CH2O)*>; ' R:RZ

[0320] CH; CH;

[0321] i

[0322] O o

[0323] (CH; CH jO R

[0324]

[0325] (OHjCH^iwR'R2 {R’"

[0326] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0327] o

[0328] _ H n

[0329] (CH2)i— N-C— (CH2)j— R2..2.

[0330] ', wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0331] In another aspect, the disclosure provides a conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0332] 27

[0333] MF-366104678Attorney Docket No.: 146392070440

[0334] (CHJCHJQJWR’R2

[0335] (GHjCHsOJmRW

[0336] O 6

[0337] CH;

[0338] R2R5 „ (OCH; CH;>rs ~G — CH; ~ C ~~ CHj ™O — Cl 1; — C — CHj — 0 ™~(C H; CH2O)*>; ' R:RZ

[0339] CH; CH;

[0340] i

[0341] O o

[0342] (CH; CH jO R

[0343]

[0344] (OHjCH^iwR'R2 {R’"

[0345] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0346] o

[0347] _ H n

[0348] (CH2) — N-C— (CH2) — R2..2.

[0349] ', wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0350] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0351] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises

[0352] 28

[0353] MF-366104678Attorney Docket No.: 146392070440

[0354] six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0355] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0356] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0357] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a)

[0358] 29

[0359] MF-366104678Attorney Docket No.: 146392070440

[0360] a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0361] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0362] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0363] 30

[0364] MF-366104678Attorney Docket No.: 146392070440

[0365] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0366] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0367] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

[0368] 31

[0369] MF-366104678Attorney Docket No.: 146392070440

[0370] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0371] CHj

[0372]

[0373] (CHJOHXOXBR’R2(CHJCHXW R'

[0374] , wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0375] O

[0376] _ _2

[0377] (CH2)I N C (CH2)J, wherein i andj are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0378] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose

[0379] 32

[0380] MF-366104678Attorney Docket No.: 146392070440

[0381] of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0382] (CHJCHJO^'R2(CH2CHzOXflH’R2

[0383] 6

[0384] CH2

[0385] R2R • “(OCHJCHJXR ~ O — CHj ~ C ~~ CH? —O ~~CHj — C —CH? -O —(CMjCHjOJm -R ’ R2

[0386] CH-> CH?

[0387] 5 =

[0388]

[0389] (GHjCHaOjmR * R2H ’ R2

[0390] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0391] o

[0392] H II

[0393] (CH2) — N~C— (CH2) — R2..2.

[0394] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0395] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or

[0396] 33

[0397] MF-366104678Attorney Docket No.: 146392070440

[0398] once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0399] < ' R“ (CHaCHxO^n H ’ R2

[0400] 9

[0401] CHJ

[0402] R2R1- (OOKJCHJ}^ ~ O — CHj ~ C ~~ CHj ~~O — CHj ~~C ~~C -O — (CHjCHjOJm -« * ft2

[0403] CH2CHJ

[0404] 5 =

[0405] O O

[0406]

[0407] (CH2CHjO)fnR * R2(CHjCHjUJm ’ R*

[0408] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0409] o

[0410] L_ H II

[0411] $ - (CH2)i— N-C— (CH2) — R2

[0412] , wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0413] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection,

[0414] 34

[0415] MF-366104678Attorney Docket No.: 146392070440

[0416] wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0417] 'f

[0418] CH? GH?

[0419] R2R ' — -(OCHjCH?;m - O ™ CHj ~C — CHj — 0 — CH j — C — CH? —O — (CHjCHjOJm -R ' R2

[0420] CH? CH?

[0421] 5 =

[0422] O p

[0423]

[0424] (CHiCHjO)f BR ’ Ra(CH? CH? O)m H1R2

[0425] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0426] o

[0427] H II

[0428] § (CH2) — N-C— (CH2)j— R2..2.

[0429] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0430] In another aspect, the disclosure provides use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein: (a) the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and (b) following (a), the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally co-administered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10, wherein each of the six

[0431] 35

[0432] MF-366104678Attorney Docket No.: 146392070440

[0433] Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:

[0434] f

[0435] fp R1— -(OCHjCH jjm ■■ O -■ CHj ~C OHj O CH j C — CH? -O (CHjCHjD )m ■• V ft2

[0436] CH? CHJ

[0437] O O

[0438]

[0439] ’ P? (CHjCMzUJrnHfR~

[0440] wherein each m is independently an integer from 10-30, wherein R1and R2when taken together has the structure

[0441] o

[0442] H II

[0443] (CH2) — N-C— (CH2)j— R2..2.

[0444] , wherein i and j are 2, and wherein each R is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

[0445] In another aspect, the disclosure provides an article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.05 mg of the conjugate, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule. In some embodiments, the container contains one unit dose of 0.05 mg of the conjugate. In some embodiments, each of the six Fabs comprises a VH

[0446] 36

[0447] MF-366104678Attorney Docket No.: 146392070440

[0448] comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0449] (CHjCHxOn R ’ R2

[0450] fp R1— -(OCHjCH j;m - O ™ CHj ~C — CHj — 0 — CH; I? ~O — (CHjCHjOJm -R1R2

[0451] CHj

[0452] 5

[0453]

[0454] wherein each m is independently an integer from 10-30,

[0455] wherein R1and R2when taken together has the structure

[0456]

[0457] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

[0458] In another aspect, the disclosure provides an article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.1 mg of the conjugate, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR- H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID

[0459] 37

[0460] MF-366104678Attorney Docket No.: 146392070440

[0461] NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule. In some embodiments, the container contains one unit dose of 0.1 mg of the conjugate. In some embodiments, each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0462] ? *

[0463] GE?

[0464] R2R5~ (OCH2CH?}W-O-“CH2~C~~ Cl-h—o— -CH2—C~-CM2“O — (GHjOHsOjm-rdn2

[0465] CH; dH;

[0466] o o

[0467]

[0468] wherein each m is independently an integer from 10-30,

[0469] wherein R1and R2when taken together has the structure

[0470] o

[0471] H II

[0472] £

[0473]

[0474] - (CH2) — N— C — (CH2)— R2

[0475] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

[0476] 38

[0477] MF-366104678Attorney Docket No.: 146392070440

[0478] In another aspect, the disclosure provides an article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.15 mg of the conjugate, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule. In some embodiments, the container contains one unit dose of 0.15 mg of the conjugate. In some embodiments, each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0479] (CHjCHjOJmR’R®(CH..Cs IR’R*

[0480] 9

[0481] CH$ 0^

[0482] o 6

[0483]

[0484] wherein each m is independently an integer from 10-30,

[0485] wherein R1and R2when taken together has the structure

[0486] o

[0487] H il

[0488] £

[0489]

[0490] - (CH2)j— N— C — (CH2)j— -R2

[0491] 39

[0492] MF-366104678Attorney Docket No.: 146392070440

[0493] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

[0494] In another aspect, the disclosure provides an article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.4 mg of the conjugate, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule. In some embodiments, the container contains one unit dose of 0.4 mg of the conjugate. In some embodiments, each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0495] 40

[0496] MF-366104678Attorney Docket No.: 146392070440

[0497] (CHJCHJQJWR’R2(CH; CH2O)mR!Rs

[0498] O 6

[0499] CH; G'H;

[0500] R2R5 „ (OCH; CH;>rs ~G — CH; - C ~~ CHj ™O — Ci ■H — C — CHj — 0 ™~(C HjCHjOyft ' R:RZ

[0501] CH; CH;

[0502] i

[0503] O o

[0504] (CH; CH jO R{R’"

[0505]

[0506] (CH2CH; O? WR'R2

[0507] wherein each m is independently an integer from 10-30,

[0508] wherein R1and R2when taken together has the structure

[0509] o

[0510] > H H

[0511] £

[0512]

[0513] (CH2)i---N~C~~(CH2)j— - R2

[0514] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

[0515] In another aspect, the disclosure provides an article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 1.3 mg of the conjugate, wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises: a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG)

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[0518] molecule. In some embodiments, the container contains one unit dose of 1.3 mg of the conjugate. In some embodiments, each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the hexameric PEG molecule has the structure of general Formula lb:

[0519] (CH^OH^KR’P?

[0520] o O

[0521] CH? CH;..

[0522] R-'- & (0CH? CH?}m-0. CH?. O. CH? ■6 Oft;? -O (OHjjCHjOJra • R:R?

[0523] Cih CHj

[0524] O 6

[0525]

[0526] (CHJCHJOJTCR’R2{CH^CHsO^R’R2

[0527] wherein each m is independently an integer from 10-30,

[0528] wherein R1and R2when taken together has the structure

[0529] o

[0530] H II

[0531] £

[0532]

[0533] - (CH2) — N-C— (CH2)j— R2

[0534] wherein i and j are 2, and wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering. In some embodiments, the container is a vial (e.g., a glass vial) or a syringe (e.g., a pre-filled syringe). In some embodiments, the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

[0535] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram showing the design of Parts 1-4 of the Phase I study. Doses of RO7446603 are shown in mg. Aflib = Aflibercept; Fari = Faricimab.

[0536] FIGs. 2A and 2B are sets of images showing the central subfield of patients in a single ascending dose regimen (FIG. 2A) or in a multiple ascending dose regimen

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[0539] (FIG. 2B) at the start of treatment (on day 1) and after the stated number of weeks following the initiation of treatment with RO7446603. BCVA = best corrected visual acuity; CST = central subfield thickness; DI = day 1; DME = diabetic macular edema; MAD = multiple ascending dose; SAD = single ascending dose; D-OCT = spectral domain optical coherence tomography; W4 = week 4; W12 = week 12.

[0540] FIGs. 3A, 3B, and 3C are graphs showing the mean aqueous humor concentration-time profiles for RO7446603 in patients following IVT injection in Part 1 (FIG. 3A), Part 2 (FIG. 3B), and Part 4 (FIG. 3C) in Study GR43828.

[0541] FIG. 4 is a graph showing pan-Akt phosphorylation on serine 473 (Ser473) of human umbilical vein endothelial cells (HUVECs) to evaluate the agonistic activity of RO7446603 on Tie2 compared with that of an inert control (anti-gD hexamer). The pAkt signal ratio is the homogeneous time -resolved fluorescence ratio of acceptor and donor emission signals multiplied by 104. Anti-gD hexamer is the negative control. The experiment was run in duplicate; the means and error ranges (calculated in a manner analogous to that used to calculate standard deviations) are shown. Circles = RO7446603; pAkt = phospho-Akt; squares = anti-gD hexamer.

[0542] FIGs. 5A and 5B are sets of graphs showing the simulated concentration in the retina of RO7446603 (FIG. 5A) and the simulated phospho-Akt (pAKT) activity (FIG.

[0543] 5B) under proposed Ph2 dosing regimens. Q4W = every four weeks; Q8W = every eight weeks.

[0544] FIG. 6 is a schematic diagram showing the design of the GR43828 study. An interim analysis can be conducted after approximately 60% of patients across all treatment arms have completed the Week 36 visit. The primary efficacy endpoint is defined as the change from baseline in best corrected visual acuity (BCVA) averaged over Weeks 52 and 56. Q4W = every four weeks; Q8W = every eight weeks; D = day; W = week; n = number of patients; mg = milligrams.

[0545] DETAILED DESCRIPTION OF THE INVENTION

[0546] The present invention provides therapeutic methods and compositions for the treatment of DME. The invention is based, at least in part, on the discovery that

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[0549] immunotherapies including an anti-Tie2 antibody conjugate can be useful in the treatment of DME. Compositions, uses, and kits involving such conjugates are also provided herein.

[0550] I. Definitions

[0551] It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0552] The term “about” as used herein in connection with a specific value (e.g., temperature, concentration, time and others) shall refer to a variation of + / - 1% of the specific value that the term “about” refers to.

[0553] A “fixed” dose of a therapeutic agent herein refers to a dose that is administered to a human patient without regard for the weight (WT) or body surface area (BSA) of the patient. The fixed dose is therefore not provided as a mg / kg dose or a mg / m2dose.

[0554] The term “antibody” encompasses various antibody structures exhibiting the desired antigen-binding activity, including but not limited to: monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments.

[0555] The term “conjugate” is used herein according to its broadest definition to mean joined or linked together. Molecules are “conjugated” when they act or operate as if joined. A “conjugate” is an antibody (e.g., Fab) conjugated to one or more heterologous molecule(s), including but not limited to a polyol, for example polyethylene glycol. In particular embodiments, “conjugate” refers to an antibody (e.g., an antibody fragment, as detailed herein) covalently bound to a multi-armed moiety. In particular embodiments, the multi-armed moiety is a polyol, an IgM molecule, or a peptide in a multimeric (e.g., hexamer) format.

[0556] The term “Tie2,” as used herein, refers to any native Tie2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,”

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[0559] unprocessed Tie2 as well as any form of Tie2 that results from processing in the cell. The term also encompasses naturally occurring variants of Tie2, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human Tie2 protein has NCBI Reference No: NP_000450 (SEQ ID NO: 23).

[0560] The terms “anti-Tie2 antibody,” an “antibody that binds to Tie2,” and “antibody that specifically binds Tie2” refer to an antibody that is capable of binding Tie2 with sufficient affinity such that the antibody is useful as a therapeutic and / or diagnostic agent in targeting Tie2. In one embodiment, the extent of binding of an anti-Tie2 antibody to an unrelated, non-Tie2 protein is less than about 10% of the binding of the antibody to Tie2 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to Tie2 has a dissociation constant (KD) of < IpM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10’8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10’13M). In certain embodiments, an anti-Tie2 antibody binds to an epitope of Tie2 that is conserved among Tie2 from different species.

[0561] The terms “conjugate that binds to Tie2,” “anti-Tie2 conjugate, ” “antibody conjugate that binds to Tie2,” and “anti-Tie2 antibody conjugate, ” refer to a conjugate having one or more anti-Tie2 antibodies or antibody fragments (e.g., one or more Fabs, e.g., six Fabs, that bind Tie2) covalently bound to a multi-armed moiety (e.g., polyethylene glycol (PEG) molecule, e.g., a hexameric PEG molecule) that is capable of binding Tie2 with sufficient affinity such that the antibody conjugate is useful as a diagnostic and / or therapeutic agent in targeting Tie2. In one aspect, the extent of binding of an anti-Tie2 conjugate to an unrelated, non-Tie2 protein is less than about 10% of the binding of the anti-Tie2 conjugate to Tie2 as measured, e.g., by surface plasmon resonance (SPR). In one aspect, each anti-Tie2 antibody or antibody fragment (e.g., Fab that binds Tie2) of an anti-Tie2 conjugate has a dissociation constant (KD) of < I pM, < 100 nM, < 10 nM, < 1 nM, <0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10’8M to 10’13M, e.g., from 10’9M to 10’13M).

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[0564] The term “full-length antibody” refers to an antibody having the structure of an immunoglobulin comprising two light chains and two heavy chains, and comprising an Fc region as defined herein. In one aspect, the antibody is a full-length IgGl antibody.

[0565] As used herein, a “Fab” refers to an antibody that comprises a heavy chain constant region that comprises the CHI domain, or a sufficient portion of the CHI domain to form a disulfide bond with the light chain constant region, but does not contain a CH2 domain or a CH3 domain. As used herein, a Fab may comprise one or more amino acids of the hinge region. Thus, as used herein, the term “Fab” encompasses Fab' antibodies. A Fab may comprise additional non-native amino acids, such as a C-terminal cysteine, in which case it may be referred to as a Fab-C. As discussed below, the term Fab-C also encompasses Fabs comprising native amino acids of the hinge region, including a native cysteine at the C-terminus. In some embodiments, a Fab comprises an engineered cysteine (i.e., a Fab may be a THIOMAB). In some embodiments, an engineered cysteine is a cysteine amino acid residue in the Fab HC and / or LC polypeptide sequence that was substituted for a noncysteine amino acid residue.

[0566] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[0567] A “humanized” antibody refers to an antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In one aspect, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of

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[0570] an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0571] “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (LC) and two identical heavy chains (HC) that are disulfide-bonded. From N- to C-terminus, each heavy chain has a heavy chain variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three heavy chain constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a light chain variable domain (VL), also called a variable light domain or a light chain variable region, followed by a light chain constant domain (CL).

[0572] An “antibody fragment” refers to a molecule other than a full-length antibody that comprises a portion of a full-length antibody that binds the antigen to which the full-length antibody binds. Examples of antibody fragments include but are not limited to Fv molecules, Fab molecules, Fab' molecules, Fab’-SH molecules, F(ab')2 molecules, diabodies, linear antibody molecules, single-chain antibody molecules (e.g., scFv and scFab molecules), and multispecific (e.g., bispecific) antibodies formed from antibody fragments.

[0573] A “multispecific antibody” is one having binding specificities for at least two different epitopes, i.e., different epitopes on different antigens or different epitopes on the same antigen. In one aspect, a multispecific antibody is a “bispecific antibody” having binding specificities for two epitopes. In one aspect, the multispecific antibody has three or more binding specificities. In one aspect, one of the binding specificities is for VEGF and the other specificity / ies is for Ang-2. In one aspect, multispecific antibodies may bind to two (or more) different epitopes of VEGF or Ang-2.

[0574] Multispecific antibodies (e.g., bispecific antibodies) may comprise antibody fragments and / or one or more Fc region. In one aspect, the multispecific antibody is the anti-VEGF / anti- Ang-2 antibody faricimab. In one aspect, the multispecific antibody is an anti- VEGF / anti- Ang-2 antibody described in U. S. Patent No.

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[0577] 9,695,233 B2, which is herein incorporated by reference in its entirety.

[0578] The terms “anti-VEGF / anti-Ang-2 antibody” and “anti-VEGF / anti-Ang-2 bispecific antibody” refer to an antibody that is capable of binding VEGF and Ang-2 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting VEGF and Ang-2. In one aspect, the extent of binding of an anti-VEGF / anti-Ang-2 antibody to an unrelated, non- VEGF, non- Ang-2 protein is less than about 10% of the binding of the antibody to VEGF or Ang-2 as measured, e.g., by surface plasmon resonance (SPR). In one aspect, an antibody that binds to VEGF has a dissociation constant (KD) of < I pM, < 100 nM, < 10 nM, < 1 nM, <0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10’8M or less, e.g., from 10’8M to 10’13M, e.g., from 10’9M to 1013M). In one aspect, an antibody that binds to Ang-2 has a dissociation constant (KD) of < I pM, < 100 nM, < 10 nM, < 1 nM, <0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10’8M or less, e.g., from 10’8M to 10’13M, e.g., from 10’9M to IO’13M).

[0579] As used herein, “faricimab” is an antibody that comprises a first antigen binding site that binds human vascular endothelial growth factor (VEGF) and comprises the heavy chain sequence of SEQ ID NO: 19 and the light chain sequence of SEQ ID NO: 20 and a second antigen binding site that binds human angiopoietin-2 (Ang-2) and comprises the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22. In some instances, the anti-VEGF / anti-Ang-2 antibody is faricimab. Faricimab is described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 118, Vol. 31, No. 4, published January 19, 2018 (see pages 672 and 673).

[0580] The term “epitope” denotes the site on an antigen, either proteinaceous or non-proteinaceous, to which an antibody binds. Epitopes can be formed both from contiguous amino acid stretches (linear epitope) or comprise non-contiguous amino acids (conformational epitope), e.g., coming in spatial proximity due to the tertiary folding of a proteinaceous antigen. Linear epitopes are typically still bound by an antibody after exposure of the proteinaceous antigen to denaturing agents, whereas conformational epitopes are typically destroyed upon treatment with denaturing

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[0583] agents. An epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation. Screening for antibodies binding to a particular epitope or determining an epitope bound by an antibody can be performed using methods known in the art such as, e.g., without limitation, alanine scanning, peptide blots (see, e.g., Reineke, Meth. Mol. Biol. 248: 443-463 (2004)), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see, e.g., Hochleitner et al., Prot. Sci. 9: 487-496 (2000)), cross-blocking (see, e.g., “Antibodies”, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., Second Edition, NY (2014)), Antigen Structure-based Antibody Profiling (ASAP), also known as Modification-Assisted Profiling (MAP) (US 2004 / 0101920), or x-ray crystallography.

[0584] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs). (See, e.g., Kindt et al. Kuby Immunology, 6thed., W. H. Freeman and Co., page 91 (2007)). A single VH or VE domain may be sufficient to confer antigenbinding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VE domain from an antibody that binds the antigen to screen a library of complementary VE or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0585] Glutamine or glutamate residues at the N-terminus of antibody heavy or light chains may be converted to pyro-glutamate spontaneously (see e.g., Liu et al., Journal of Pharmaceutical Sciences 97, 2426-2447 (2008), Rehder et al., Journal of Chromatography A 1102, 164-175 (2006), Chelius et al., Anal Chem 78, 2370-2376 (2006)). Hence, variable domains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus of the antibody heavy or light chain, may comprise an N-terminal pyro-glutamate (pyroE) residue instead of the N-terminal Q or E residue. Likewise, antibody heavy chains or light chains disclosed

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[0588] herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus, may comprise an N-terminal pyro-glutamate (pyroE) residue instead of the N-terminal Q or E residue. Accordingly, for each antibody heavy chain, light chain, or variable domain sequence disclosed herein that contains an N-terminal Q or E residue, the corresponding sequence with an N-terminal pyroE residue is also encompassed.

[0589] A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat, E. A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) NIH Publication 91-3242 (hereinafter “Kabat 1991”). In one aspect, for the VL, the subgroup is subgroup kappa I as in Kabat 1991. In one aspect, for the VH, the subgroup is subgroup III as in Kabat 1991.

[0590] The term “complementarity determining region” or “CDR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity. Generally, antibodies comprise six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). CDRs are defined by a variety of methods / sy stems by those skilled in the art. These systems and / or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM, and Contact. The Kabat definition is based on sequence variability and generally is the most commonly used. The Chothia definition is based on the location of the structural loop regions. The IMGT system is based on sequence variability and location within the structure of the variable domain. The AbM definition is a compromise between Kabat and Chothia. The Contact definition is based on analyses of the available antibody crystal structures. Software programs (e.g., abYsis: http: / / www.abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi) are

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[0593] available and known to those of skill in the art for analysis of antibody sequences and determination of CDRs.

[0594] Exemplary CDRs herein include (numbering of amino acid residues according to the reference cited, i.e. Chothia numbering for the Chothia and Contact definition, Kabat numbering for the Kabat definition and IMGT numbering for the IMGT definition):

[0595] (a) hypervariable loops occurring at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 (H3), according to Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987) (“Chothia definition”);

[0596] (b) CDRs occurring at amino acid residues 24-34 (LI), 50-56 (L2), 89-97 (L3), 31-35B (Hl), 50-65 (H2), and 95-102 (H3), according to Kabat 1991 (“Kabat definition”);

[0597] (c) antigen contacts occurring at amino acid residues 30-36 (LI), 46-55 (L2), 89-96 (L3), 30-35 (Hl), 47-58 (H2), and 93-101 (H3), according to MacCallum et al. J. Mol. Biol. 262: 732-745 (1996) (“Contact definition”); and

[0598] (d) CDRs occurring at amino acid residues 27-38 (LI), 56-65 (L2), 105-117 (L3), 27-38 (Hl), 56-65 (H2), and 105-117 (H3), according to Lefranc et al. Dev. Comp. Immunol. 27: 55-77 (2003) (“IMGT definition”).

[0599] Unless otherwise indicated, the CDRs are determined herein according to Kabat 1991. One of skill in the art will understand that the CDR designations can also be determined according to Chothia, MacCallum, Lefranc, or any other scientifically accepted definition / system.

[0600] “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.

[0601] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses

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[0604] (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain.

[0605] The terms “constant region derived from human origin” or “human constant region” as used herein denotes a constant region of a human antibody, in particular a heavy chain constant region of a human antibody of the subclass IgGl, IgG2, IgG3, or IgG4 and / or a light chain kappa or lambda constant region. Such constant regions are well known in the state of the art and e.g., described by Kabat 1991.

[0606] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case in particular where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, Kabat EU numbering). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Unless stated otherwise herein, references to residue numbers in the variable domain of antibodies means residue numbering by the Kabat numbering system.

[0607] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or a constant region is according to the EU numbering system, also called the EU index, as described in Kabat 1991.

[0608] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner

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[0611] (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. A preferred method for measuring affinity is Surface Plasmon Resonance (SPR).

[0612] An “isolated” antibody is one which has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC, affinity chromatography, size exclusion chromatography) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0613] A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

[0614] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0615] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purposes of the alignment. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, Clustal W, MegAlign (DNASTAR) software or the FASTA program package. Those

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[0618] skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Alternatively, the percent identity values can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U. S. Copyright Office, Washington D. C., 20559, where it is registered under U. S. Copyright Registration No. TXU510087 and is described in WO 2001 / 007611.

[0619] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values are generated using the ggsearch program of the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix. The FASTA program package was authored by W. R. Pearson and D. J. Lipman (1988), “Improved Tools for Biological Sequence Analysis” Proc. Nat. Acad. Sci. 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et. al. (1997) Genomics 46:24-36 and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www. ebi.ac.uk / Tools / sss / fasta. Alternatively, a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi can be used to compare the sequences, using the ggsearch (global protein: protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global, rather than local, alignment is performed. Percent amino acid identity is given in the output alignment header.

[0620] As used herein, the term “treatment” refers to clinical intervention in an attempt to alter the natural course of a disease during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For purposes of this disclosure, beneficial or desired clinical results include reduction or improvement in signs and symptoms of DME, for example as compared to before administration of an anti-Tie2 antibody conjugate described herein.

[0621] 54

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[0623] An “effective amount” of an agent, e.g., a pharmaceutical composition, refers to an amount of the antibody or medicament effective, at dosages and for periods of time necessary, to achieve the desired treatment as defined above.

[0624] A “patient,” an “individual,” or a "subject," used interchangeably herein, is a mammal. In one aspect, the individual or subject is a human. In one aspect, the individual is in need of treatment with the medicament, antibody, and / or conjugate disclosed herein.

[0625] The term “pharmaceutical composition” or “pharmaceutical formulation” refers to a preparation of the antibody and one or more pharmaceutically acceptable carriers or excipients.

[0626] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject and includes, but is not limited to, a buffer, excipient, stabilizer, surfactant, and / or preservative.

[0627] II. Methods of Treating Diabetic Macular Edema with anti-Tie2 Antibody Conjugates

[0628] The disclosure provides methods of treating DME in a human patient in need thereof comprising intravitreally administering (i.e., via intravitreal (IVT) injection) to the human patient one or more fixed doses of an effective amount of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603).

[0629] In some aspects, the disclosure provides a method of treating a DME in a human patient, the method comprising intravitreally administering (i.e., via IVT injection) to the human patient one or more fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603). As would be understood by one of ordinary skill in the art, references herein to the amount of a dose e.g., fixed dose) of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and / or an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody

[0630] 55

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[0632] provided in Section IV herein, e.g., faricimab) refer to the amount to be administered per eye, e.g., in a single IVT injection.

[0633] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen.

[0634] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III

[0635] 56

[0636] MF-366104678Attorney Docket No.: 146392070440

[0637] herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen.

[0638] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2

[0639] 57

[0640] MF-366104678Attorney Docket No.: 146392070440

[0641] antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen.

[0642] In some aspects, the method further comprises IVT administration of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) is intravitreally administered (i.e., via IVT injection) at a dose of 6 mg per eye.

[0643] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months),

[0644] 58

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[0646] wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0647] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of

[0648] 59

[0649] MF-366104678Attorney Docket No.: 146392070440

[0650] the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0651] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is

[0652] 60

[0653] MF-366104678Attorney Docket No.: 146392070440

[0654] intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0655] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody

[0656] 61

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[0658] conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0659] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months),

[0660] 62

[0661] MF-366104678Attorney Docket No.: 146392070440

[0662] intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and

[0663] 63

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[0665] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0666] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-

[0667] 64

[0668] MF-366104678Attorney Docket No.: 146392070440

[0669] Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0670] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g.,

[0671] 65

[0672] MF-366104678Attorney Docket No.: 146392070440

[0673] faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0674] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co- administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the

[0675] 66

[0676] MF-366104678Attorney Docket No.: 146392070440

[0677] human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0678] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered

[0679] 67

[0680] MF-366104678Attorney Docket No.: 146392070440

[0681] (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0682] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses,

[0683] 68

[0684] MF-366104678Attorney Docket No.: 146392070440

[0685] followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-

[0686] 69

[0687] MF-366104678Attorney Docket No.: 146392070440

[0688] VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0689] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody

[0690] 70

[0691] MF-366104678Attorney Docket No.: 146392070440

[0692] conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0693] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.05 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT

[0694] 71

[0695] MF-366104678Attorney Docket No.: 146392070440

[0696] injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0697] The disclosure also provides a method of treating a DME in a human patient, the method comprising intravitreally administering (i.e., via IVT injection) to the human patient one or more fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603).

[0698] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four

[0699] 72

[0700] MF-366104678Attorney Docket No.: 146392070440

[0701] (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen.

[0702] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in

[0703] 73

[0704] MF-366104678Attorney Docket No.: 146392070440

[0705] Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen.

[0706] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in

[0707] 74

[0708] MF-366104678Attorney Docket No.: 146392070440

[0709] Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen.

[0710] In some aspects, the method further comprises IVT administration of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) is intravitreally administered (i.e., via IVT injection) at a dose of 6 mg per eye.

[0711] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances,

[0712] 75

[0713] MF-366104678Attorney Docket No.: 146392070440

[0714] an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0715] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab).

[0716] 76

[0717] MF-366104678Attorney Docket No.: 146392070440

[0718] In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0719] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody

[0720] 77

[0721] MF-366104678Attorney Docket No.: 146392070440

[0722] conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0723] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody

[0724] 78

[0725] MF-366104678Attorney Docket No.: 146392070440

[0726] provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0727] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months),

[0728] 79

[0729] MF-366104678Attorney Docket No.: 146392070440

[0730] intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0731] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific

[0732] 80

[0733] MF-366104678Attorney Docket No.: 146392070440

[0734] antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0735] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four

[0736] 81

[0737] MF-366104678Attorney Docket No.: 146392070440

[0738] doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and

[0739] 82

[0740] MF-366104678Attorney Docket No.: 146392070440

[0741] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0742] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered

[0743] 83

[0744] MF-366104678Attorney Docket No.: 146392070440

[0745] (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0746] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co- administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-

[0747] 84

[0748] MF-366104678Attorney Docket No.: 146392070440

[0749] 2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0750] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per

[0751] 85

[0752] MF-366104678Attorney Docket No.: 146392070440

[0753] eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0754] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises

[0755] 86

[0756] MF-366104678Attorney Docket No.: 146392070440

[0757] intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0758] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2

[0759] 87

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[0761] antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.1 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g.,

[0762] 88

[0763] MF-366104678Attorney Docket No.: 146392070440

[0764] an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0765] The disclosure also provides a method of treating a DME in a human patient, the method comprising intravitreally administering (i.e., via IVT injection) to the human patient one or more fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603).

[0766] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen.

[0767] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months),

[0768] 89

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[0770] intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen.

[0771] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g.,

[0772] 90

[0773] MF-366104678Attorney Docket No.: 146392070440

[0774] RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen.

[0775] In some aspects, the method further comprises IVT administration of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the anti-VEGF / anti-Ang-2 bispecific

[0776] 91

[0777] MF-366104678Attorney Docket No.: 146392070440

[0778] antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) is intravitreally administered (i.e., via IVT injection) at a dose of 6 mg per eye.

[0779] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-

[0780] 92

[0781] MF-366104678Attorney Docket No.: 146392070440

[0782] VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0783] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti- VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and

[0784] 93

[0785] MF-366104678Attorney Docket No.: 146392070440

[0786] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0787] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and

[0788] 94

[0789] MF-366104678Attorney Docket No.: 146392070440

[0790] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0791] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For

[0792] 95

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[0794] example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0795] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2

[0796] 96

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[0798] bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0799] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an

[0800] 97

[0801] MF-366104678Attorney Docket No.: 146392070440

[0802] anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0803] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided

[0804] 98

[0805] MF-366104678Attorney Docket No.: 146392070440

[0806] in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0807] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with

[0808] 99

[0809] MF-366104678Attorney Docket No.: 146392070440

[0810] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0811] 100

[0812] MF-366104678Attorney Docket No.: 146392070440

[0813] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered

[0814] 101

[0815] MF-366104678Attorney Docket No.: 146392070440

[0816] (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0817] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an

[0818] 102

[0819] MF-366104678Attorney Docket No.: 146392070440

[0820] antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0821] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in

[0822] 103

[0823] MF-366104678Attorney Docket No.: 146392070440

[0824] Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0825] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six

[0826] 104

[0827] MF-366104678Attorney Docket No.: 146392070440

[0828] doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.15 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0829] The disclosure also provides a method of treating a DME in a human patient, the method comprising intravitreally administering (i.e., via IVT injection) to the human patient one or more fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603).

[0830] 105

[0831] MF-366104678Attorney Docket No.: 146392070440

[0832] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen.

[0833] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an

[0834] 106

[0835] MF-366104678Attorney Docket No.: 146392070440

[0836] anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen.

[0837] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per

[0838] 107

[0839] MF-366104678Attorney Docket No.: 146392070440

[0840] eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen.

[0841] In some aspects, the method further comprises IVT administration of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) is intravitreally administered (i.e., via IVT injection) at a dose of 6 mg per eye.

[0842] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific

[0843] 108

[0844] MF-366104678Attorney Docket No.: 146392070440

[0845] antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0846] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody

[0847] 109

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[0849] provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0850] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab).

[0851] 110

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[0853] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0854] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV

[0855] 111

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[0857] herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0858] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in

[0859] 112

[0860] MF-366104678Attorney Docket No.: 146392070440

[0861] Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the one or more fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0862] 113

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[0864] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an

[0865] 114

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[0867] antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0868] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate

[0869] 115

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[0871] provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0872] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen, intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four

[0873] 116

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[0875] weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0876] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally

[0877] 117

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[0879] administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0880] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once

[0881] 118

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[0883] every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0884] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g.,

[0885] 119

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[0887] an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and

[0888] 120

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[0890] an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0891] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen, followed by intravitreally administering a fixed dose of 0.4 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For

[0892] 121

[0893] MF-366104678Attorney Docket No.: 146392070440

[0894] example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0895] The disclosure also provides a method of treating a DME in a human patient, the method comprising intravitreally administering (i.e., via IVT injection) to the human patient one or more fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603).

[0896] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses. In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses

[0897] 122

[0898] MF-366104678Attorney Docket No.: 146392070440

[0899] of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen.

[0900] In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for at least four doses, intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) for four doses, intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses. In some aspects, the method comprises, prior to intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every two months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of a dosing regimen,

[0901] 123

[0902] MF-366104678Attorney Docket No.: 146392070440

[0903] intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every four weeks for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of the dosing regimen.

[0904] In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months). In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for at least four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) for four doses. In some aspects, the method comprises intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 4 weeks (or once every month) for the first six doses in each of Weeks 0, 4, 8, 12, 16, 20 (e.g., on day 1 of each of Weeks 0, 4, 8, 12, 16, 20) of a dosing regimen,

[0905] 124

[0906] MF-366104678Attorney Docket No.: 146392070440

[0907] followed by intravitreally administering a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every 8 weeks (or once every 2 months) in each of Weeks 28, 36, 44, and 52 (e.g., on day 1 of each of Weeks 28, 36, 44, and 52) of the dosing regimen.

[0908] In some aspects, the method further comprises IVT administration of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) is intravitreally administered (i.e., via IVT injection) at a dose of 6 mg per eye.

[0909] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient a fixed dose of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months), wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an

[0910] 125

[0911] MF-366104678Attorney Docket No.: 146392070440

[0912] antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0913] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for at least four (e.g., 4, 5, 6, 7, 8, 9, 10, or more) doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2

[0914] 126

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[0916] bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0917] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) once every eight weeks (or once every two months) for four doses, wherein each of the fixed doses of the anti-Tie2 antibody conjugate is intravitreally co-administered (i.e., via IVT injection) with 6 mg per eye of an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab). In some instances, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) together. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab)

[0918] 127

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[0920] can be co-mixed and administered as a single IVT injection. In some aspects, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) are intravitreally administered (i.e., via IVT injection) separately. For example, an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein, e.g., RO7446603) and an anti-VEGF / anti-Ang-2 bispecific antibody (e.g., an antibody provided in Section IV herein, e.g., faricimab) can be administered as separate IVT injections.

[0921] In some aspects, the method comprises intravitreally administering (i.e., via IVT injection) to the human patient fixed doses of 1.3 mg per eye of an anti-Tie2 antibody conjugate (e.g., an anti-Tie2 antibody conjugate provided in Section III herein,...

Claims

Attorney Docket No.: 146392070440 WHAT IS CLAIMED IS:

1. A method of treating diabetic macular edema (DME) in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.05 mg per eye of a conjugate that binds tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (Tie2),wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

2. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.05 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.313MF-366104678Attorney Docket No.: 1463920704403. The method of claim 1 or 2, comprising intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every two months).

4. The method of claim 3, comprising, prior to intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every four weeks for the first six doses.

5. The method of claim 1 or 2, comprising intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

6. The method of any one of claims 3-5, wherein a fixed dose of 0.05 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

7. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.1 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-314MF-366104678Attorney Docket No.: 146392070440LI comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

8. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.1 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

9. The method of claim 7 or 8, comprising intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every two months).

10. The method of claim 9, comprising, prior to intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every four weeks for the first six doses.

11. The method of claim 7 or 8, comprising intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months).315MF-366104678Attorney Docket No.: 14639207044012. The method of any one of claims 9-11, wherein a fixed dose of 0.1 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

13. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.15 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

14. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.15 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.316MF-366104678Attorney Docket No.: 14639207044015. The method of claim 13 or 14, comprising intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every two months).

16. The method of claim 15, comprising, prior to intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every four weeks for the first six doses.

17. The method of claim 13 or 14, comprising intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

18. The method of any one of claims 15-17, wherein a fixed dose of 0.15 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

19. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.4 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-317MF-366104678Attorney Docket No.: 146392070440LI comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

20. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 0.4 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

21. The method of claim 19 or 20, comprising intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every two months).

22. The method of claim 21, comprising, prior to intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every four weeks for the first six doses.

23. The method of claim 19 or 20, comprising intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months).318MF-366104678Attorney Docket No.: 14639207044024. The method of any one of claims 21-23, wherein a fixed dose of 0.4 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

25. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 1.3 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a VL comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), and wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

26. A method of treating DME in a human patient in need thereof, the method comprising intravitreally administering to the human patient one or more fixed dose(s) of 1.3 mg per eye of a conjugate that binds Tie2, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.319MF-366104678Attorney Docket No.: 14639207044027. The method of claim 25 or 26, comprising intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every two months).

28. The method of claim 27, comprising, prior to intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every two months), intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every four weeks for the first six doses.

29. The method of claim 25 or 26, comprising intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses, followed by intravitreally administering a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months).

30. The method of any one of claims 27-29, wherein a fixed dose of 1.3 mg per eye of the conjugate is intravitreally administered to the human patient once every 8 weeks (or once every two months) for at least four doses.

31. The method of any one of claims 1-30, wherein each of the one or more fixed dose(s) of the conjugate are intravitreally co-administered with faricimab.

32. The method of claim 31, wherein each of the one or more fixed dose(s) of the conjugate are intravitreally co-administered with 6 mg faricimab per eye.320MF-366104678Attorney Docket No.: 14639207044033. The method of claim 31, wherein the co-administration comprises administration of the conjugate and the faricimab together or separately.

34. The method of claim 31, wherein the conjugate and the faricimab are (a) co-mixed and administered as a single intravitreal (IVT) injection; or (b) administered as separate IVT injections.

35. The method of any one of claims 1, 3-7, 9-13, 15-19, 21-25, and 27-34, wherein (a) the VH of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7; or (b) the VL of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8.

36. The method of any one of claims 1, 3-7, 9-13, 15-19, 21-25, and 27-34, wherein the VH of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7 and the VL of each of the six Fabs comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8.

37. The method of claim 36, wherein (a) the VH of each of the six Fabs comprises the amino acid sequence of SEQ ID NO: 7; and (b) the VL of each of the six Fabs comprises the amino acid sequence of SEQ ID NO: 8.

38. The method of any one of claims 1-37, wherein each of the six Fabs comprises (a) a Fab heavy chain (HC) comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; (b) a Fab light chain (LC) comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10; or (c) a Fab HC comprising an amino acid sequence having at least 95% sequence identity to SEQ321MF-366104678Attorney Docket No.: 146392070440ID NO: 9 and a Fab LC comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10.

39. The method of any one of claims 1-38, wherein each of the six Fabs comprises (a) a Fab HC comprising the amino acid sequence of SEQ ID NO: 9; (b) a Fab LC comprising the amino acid sequence of SEQ ID NO: 10; or (c) a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10.

40. The method of any one of claims 1-39, wherein each of the six Fabs comprises a Fab HC and a Fab LC, and wherein each of the six Fabs is linked to a different arm of the hexameric PEG molecule through a free sulfhydryl group of a cysteine amino acid residue at:(a) position 120, 166, 178, 187, or 209 in the Fab HC; or(b) position 124, 142, 155, 201, 206, 107, 126, or 149 in the Fab LC, wherein the residue number is according to EU numbering.

41. The method of claim 40, wherein each of the six Fabs is linked to a different arm of the hexameric PEG molecule through a free sulfhydryl group of a cysteine amino acid residue at position 209 in each Fab HC, wherein the residue number is according to EU numbering.

42. The method of any one of claims 1-41, wherein the hexameric PEG molecule has an average molecular weight of about 500 Daltons (Da) to about 300,000 Da.

43. The method of claim 42, wherein the hexameric PEG molecule has an average molecular weight of about 1000 Da to about 10,000 Da.322MF-366104678Attorney Docket No.: 14639207044044. The method of any one of claims 1-43, wherein the hexameric PEG molecule has the structure of general formula lb:{CHjC^Ojms^FC6 4oCH; CH;R2R5— (C”CH; CH;)? C'‘‘O‘‘‘‘CH; -C. CH;. O. CH?. C CH; - O (CH; CH; G}m -ft5R2CH? CH?6 o1iCH;0H; C}mH(CHjCHsOlmR ’RAwherein each m is independently an integer from 3-250; each R1is independently either absent or is a linking group; and each R2is independently either hydrogen or a terminal reactive group; andwherein at least one R2is a terminal reactive group and is covalently linked to one of the six Fabs.

45. The method of claim 44, wherein each R2is a terminal reactive group and is covalently linked to the Fab HC of each of the Fabs.

46. The method of claim 44 or 45, wherein each R2is a maleimide and is covalently linked to the Fab HC of each of the Fabs.

47. The method of any one of claims 1-46, wherein the hexameric PEG molecule has the structure of general formula lb:(CHjCMsOtmR1R'6CH;f? RHOCHZCW: “O -CH;. ~C —CH; — -G— CH; {CH;CHjO(CHgCH^O’SnR’R-(CH; CH; O}m3 FC wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structure:323MF-366104678Attorney Docket No.: 146392070440oH II£— (CH2) — N-C— (CH2) — R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of the Fab HC of the Fab, wherein the residue number is according to EU numbering.

48. A method of treating DME in a human patient in need thereof, the method comprising:(a) intravitreally administering to the human patient a fixed dose of 0.05 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and(b) following (a), intravitreally administering a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:? OCHJ CH?.CH2~~ C~~CH2~O — {CHJCH2O^-RN2CH? CH2i '!q owherein each m is independently an integer from 10-30,324MF-366104678Attorney Docket No.: 146392070440wherein R1and R2when taken together has the structureoH II£— (CH2) — N-C— (CH2)— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

49. A method of treating DME in a human patient in need thereof, the method comprising:(a) intravitreally administering to the human patient a fixed dose of 0.1 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and(b) following (a), intravitreally administering a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:? o ’GH?.

0. CH? ■■■■<;. CH3-C. {CHaCHjOJm-ft’R2CH? CH?i " S 'o o325MF-366104678Attorney Docket No.: 146392070440wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II£(CH2)i— N— C — (CH2) — R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

50. A method of treating DME in a human patient in need thereof, the method comprising:(a) intravitreally administering to the human patient a fixed dose of 0.15 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and(b) following (a), intravitreally administering a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:326MF-366104678Attorney Docket No.: 146392070440wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH H£{CH2)i“N- - C — (CH2);”R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

51. A method of treating DME in a human patient in need thereof, the method comprising:(a) intravitreally administering to the human patient a fixed dose of 0.4 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and(b) following (a), intravitreally administering a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,327MF-366104678Attorney Docket No.: 146392070440wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:{CHjCH^Ojms^FC6 4O CH? CH?R2R5■■■; OCH2CH?)?^"0--CH2-C O CH?. C CHj - O (CH2CH2O}m -ft5R2CH? CH?6 o iCH?0H2C}mH ’R(CHjCHsOtrnR1fVAwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II3(CH2)i— N— c — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

52. A method of treating DME in a human patient in need thereof, the method comprising:(a) intravitreally administering to the human patient a fixed dose of 1.3 mg per eye of a conjugate that binds Tie2 once every 4 weeks (or once every month) for the first six doses; and(b) following (a), intravitreally administering a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are co-mixed and administered as a single IVT injection,wherein the conjugate comprises six Fabs that bind Tie2,328MF-366104678Attorney Docket No.: 146392070440wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:O I O CH?. CH?r >R2R ' ~~ —CHj ~C — CH2—O — CHj — C — CH j — O — (C HjC HjOJmCH? CH?I '■6 oi Xwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureo> H II£(CH2)i— N-C — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

53. The method of any one of claims 1-52, wherein the treatment results in an improvement from baseline in best-corrected visual acuity (BCVA).

54. The method of any one of claims 1-53, wherein the treatment results in an improvement from baseline in central subfield thickness (CST).

55. A kit comprising a conjugate that binds Tie2 and a package insert comprising instructions for using the conjugate for treating DME in an individual in need thereof according to the method of any one of claims 1-54.329MF-366104678Attorney Docket No.: 14639207044056. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

57. A conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

58. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,330MF-366104678Attorney Docket No.: 146392070440wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

59. A conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

60. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain331MF-366104678Attorney Docket No.: 146392070440(VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

61. A conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

62. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.332MF-366104678Attorney Docket No.: 14639207044063. A conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

64. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

65. A conjugate that binds Tie2 for use in a method of treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient,333MF-366104678Attorney Docket No.: 146392070440wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

66. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:V o^Rt~(0CH2Cri2)a:~O“CHj“C~“CH2~'0““CH2~“C~“CH2"0 — {CHjClfeO^’R^2CH? CH-si '!o owherein each m is independently an integer from 10-30,334MF-366104678Attorney Docket No.: 146392070440wherein R1and R2when taken together has the structureoH II£— (CH2) — N-C— (CH2)— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

67. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:(CH? CH2OMpR2? o ’CH?.

0. -CH? ■■■■<;. CHJ-CJ. (CH? CH2O}mHi:(R2CH? CH?i " S 'o o335MF-366104678Attorney Docket No.: 146392070440wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II£(CH2)i— N— C — (CH2) — R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

68. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,336MF-366104678Attorney Docket No.: 146392070440wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:{CHjCH^Ojms^FC6 3O CH? CH?R2R5■■■; OCH2CH?)?^"0--CH2-C O CH?. C CHj - O (CH2CH2O}m -ft5R2CH? CH?6 o iCH?0H2C}mH ’R(CHjCHsOtrnR1fVAwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II3(CH2)i— N— c — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

69. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,337MF-366104678Attorney Docket No.: 146392070440wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:O IOcsy CH?r >R2R ' ~~ —CHj ~C — CH2—O — CHj — C — CH j — O — (C HjC HjOJmCH? CH?I '■6 oi Xwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureo> H II£(CH2)i— N-C — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

70. A conjugate that binds Tie2 for use in treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection,338MF-366104678Attorney Docket No.: 146392070440wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:GH?i IR ’ ~ ((X H? CH?>n ~O “CH? ~ C ™ C H;< —0 — CH? —C —CH?. ~ C — (CHjCHjCJm -R ’R*CH? CH?6 O(CH?. CH? O)!nRM2(CHJCH^GXBR'R'wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH H(CH2)i— N-C — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

71. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino339MF-366104678Attorney Docket No.: 146392070440acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

72. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.05 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

73. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ340MF-366104678Attorney Docket No.: 146392070440ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

74. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.1 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

75. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.341MF-366104678Attorney Docket No.: 14639207044076. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.15 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

77. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

78. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 0.4 mg per eye of the conjugate are to be intravitreally administered to the human patient,342MF-366104678Attorney Docket No.: 146392070440wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

79. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises:a VH comprising (a) a CDR-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

80. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein one or more fixed dose(s) of 1.3 mg per eye of the conjugate are to be intravitreally administered to the human patient,wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and343MF-366104678Attorney Docket No.: 146392070440wherein each of the Fabs is linked to an arm of a hexameric PEG molecule.

81. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.05 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:(CHxCHsOMVfVSjsT: ~O —CH; CH;{CH; wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH H- (CH2)i— N— C — (CH2)j — R2wherein i and j are 2, and344MF-366104678Attorney Docket No.: 146392070440wherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

82. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.1 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:« i ' ■CH2R2Ri~(0CH2CHi.kf:~O~'CH»~C~CH2'~0 — CH?~~C~~CH2”O — {CH / CHjOisn-RN2i §CH- / Crhi ■!Q O(CH2CH?. O^R!RJ’«'■wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II£(CH2) — N-C— (CH2)j— R2345MF-366104678Attorney Docket No.: 146392070440wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

83. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.15 mg per eye of the conjugate once every 8 weeks (or once every 2 months),wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:,...u O(.CH? CH?R;' R ’ - (OC H? CH?>« ~O ~~CH? -C—CHj ~~O — CH? ~~ C —CH? ~O — (CH? CH *R5R ’Cf+> CH?i IO Qwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structure346MF-366104678Attorney Docket No.: 146392070440o£ H II5(CH2)j— N— C — (CH2)j— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

84. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 0.4 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:? oCHJ CH?.CH2~~ C~~CH2~O — {Cf l2CH2O)sn-RN^CH? CH2i '!q o(CH2CH2O}mR!R3(CH2CH2OfenR-R2wherein each m is independently an integer from 10-30,347MF-366104678Attorney Docket No.: 146392070440wherein R1and R2when taken together has the structureoH II£— (CH2) — N-C— (CH2)— R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

85. Use of a conjugate that binds Tie2 in the manufacture of a medicament for treating DME in a human patient in need thereof, wherein:(a) the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 4 weeks (or once every month) for the first six doses; and(b) following (a), the human patient is to be intravitreally administered a fixed dose of 1.3 mg per eye of the conjugate once every 8 weeks (or once every 2 months), wherein each of the fixed doses of the conjugate is to be intravitreally coadministered with 6 mg faricimab per eye, and wherein the conjugate and the faricimab are to be co-mixed and administered as a single IVT injection, wherein the conjugate comprises six Fabs that bind Tie2,wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10,wherein each of the six Fabs is linked to an arm of a hexameric PEG molecule, wherein the hexameric PEG molecule has the structure of general Formula lb:? o ’GH?.

0. CH? ■■■■<;. CH3-C. {CHaCHjOJm-ft’R2CH? CH?i " S 'o o348MF-366104678Attorney Docket No.: 146392070440wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II£- (CH2)i— N— C — (CH2) — R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

86. An article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.05 mg of the conjugate,wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-H1 comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

87. The article of manufacture of claim 86, wherein the container contains one unit dose of 0.05 mg of the conjugate.349MF-366104678Attorney Docket No.: 14639207044088. An article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.1 mg of the conjugate,wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

89. The article of manufacture of claim 88, wherein the container contains one unit dose of 0.1 mg of the conjugate.

90. An article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.15 mg of the conjugate,wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain350MF-366104678Attorney Docket No.: 146392070440(VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

91. The article of manufacture of claim 90, wherein the container contains one unit dose of 0.15 mg of the conjugate.

92. An article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 0.4 mg of the conjugate,wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

93. The article of manufacture of claim 92, wherein the container contains one unit dose of 0.4 mg of the conjugate.351MF-366104678Attorney Docket No.: 14639207044094. An article of manufacture, comprising a container that contains an amount of a conjugate that binds Tie2 sufficient for administration of a unit dose of 1.3 mg of the conjugate,wherein the conjugate comprises six Fabs that bind Tie2, wherein each of the six Fabs comprises:a heavy chain variable domain (VH) comprising (a) a complementarity determining region (CDR)-Hl comprising the amino acid sequence NTDIS (SEQ ID NO: 1), (b) a CDR-H2 comprising the amino acid sequence RISPSDGNTYYADSVKG (SEQ ID NO: 2), and (c) a CDR-H3 comprising the amino acid sequence RTRWASWAFDY (SEQ ID NO: 3), and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 4), (e) a CDR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 5), and (f) a CDR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 6), andwherein each of the Fabs is linked to an arm of a hexameric polyethylene glycol (PEG) molecule.

95. The article of manufacture of claim 94, wherein the container contains one unit dose of 1.3 mg of the conjugate.

96. The article of manufacture of any one of claims 86-95, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8.

97. The article of manufacture of any one of claims 86-96, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10.352MF-366104678Attorney Docket No.: 14639207044098. The article of manufacture of any one of claims 86-97, wherein the hexameric PEG molecule has the structure of general Formula lb:{CHjCH^Ojms^FC6 3O CH? CH?R2«5■■■; OCH2CH?)?^"0--CH2-C. CW2. O. CH?. C CHj - O (CH2CHjO}m -ft5R2CH? CH?6 oiCH?0HjC}mS(CHjCHsOtrnR1fV ’RAwherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH H(CH2)i— N— C — (CH2)j — R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

99. The article of manufacture of any one of claims 86-98, wherein the container is a vial.

100. The article of manufacture of any one of claims 86-98, wherein the container is a syringe.

101. The article of manufacture of any one of claims 86-100, wherein the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

102. The kit of claim 55, wherein the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.05 mg of the conjugate.353MF-366104678Attorney Docket No.: 146392070440103. The kit of claim 55, wherein the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.1 mg of the conjugate.

104. The kit of claim 55, wherein the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.15 mg of the conjugate.

105. The kit of claim 55, wherein the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 0.4 mg of the conjugate.

106. The kit of claim 55, wherein the conjugate is in a container that contains an amount of the conjugate sufficient for administration of a unit dose of 1.3 mg of the conjugate.

107. The kit of any one of claims 55 and 102-106, wherein each of the six Fabs comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8.

108. The kit of any one of claims 55 and 102-107, wherein each of the six Fabs comprises a Fab HC comprising the amino acid sequence of SEQ ID NO: 9 and a Fab LC comprising the amino acid sequence of SEQ ID NO: 10.

109. The kit of any one of claims 55 and 102-108, wherein the hexameric PEG molecule has the structure of general Formula lb:354MF-366104678Attorney Docket No.: 146392070440wherein each m is independently an integer from 10-30,wherein R1and R2when taken together has the structureoH II£- (CH2)i~ -N~~ C~ ~(CH2)j“R2wherein i and j are 2, andwherein each R2is a maleamide and is covalently linked to one of the six Fabs through a free sulfhydryl group of a cysteine amino acid residue at position 209 of each Fab HC, wherein the residue number is according to EU numbering.

110. The kit of any one of claims 55 and 102-109, wherein the container is a vial.

111. The kit of any one of claims 55 and 102-109, wherein the container is a syringe.

112. The kit of any one of claims 102- 111, further comprising a second container that contains one or more unit dose(s) of faricimab.

113. The kit of claim 112, wherein the second container contains a unit dose of 6 mg faricimab.

114. The kit of any one of claims 102- 111, wherein the instructions indicate that the conjugate is to be administered in combination with faricimab.355MF-366104678Attorney Docket No.: 146392070440115. The kit of claim 114, wherein the instructions indicate that the conjugate is to be administered in combination with one or more unit dose(s) of 6 mg faricimab per eye.

116. The kit of any one of claims 102-111, wherein the container further comprises an amount of faricimab sufficient for administration of a unit dose of 6 mg of faricimab.

117. The method of any one of claims 1-46, 53, or 54, the kit of any one of claims 55, 102-108, or 110-116, the conjugate for use of any one of claims 56-66, the use of any one of claims 71-80, the article of manufacture of any one of claims 86-97, 99, or 100, wherein the conjugate has the structure of formula Ic:356MF-366104678Attorney Docket No.: 146392070440118. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein each m is independently an integer from about 10 to about 30.

119. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein each m is independently an integer from about 13 to about 23.

120. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 1 to about 35.

121. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 10 to about 30.

122. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 13 to about 23.

123. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 16 to about 20.

124. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 17-18.

125. The method, kit, conjugate, use, or article of manufacture of claim 117, wherein the average of m is about 18.

126. The method, kit, conjugate, use, or article of manufacture of any one of claims 117-125, wherein the portion of the conjugate lacking the Fabs has the structure of formula Id:357MF-366104678Attorney Docket No.: 146392070440127. The method, kit, conjugate, use, or article of manufacture of claim 126, wherein the portion of the conjugate lacking the Fabs has an Mwof about 1675 to about 10,000 Da.

128. The method, kit, conjugate, use, or article of manufacture of claim 126, wherein the portion of the conjugate lacking the Fabs has an Mwof about 5400 to about 6600 Da.

129. The method, kit, conjugate, use, or article of manufacture of any one of claims 117-128, wherein the conjugate has an Mwof about 283 kDa to 293 kDa.358MF-366104678Attorney Docket No.: 146392070440130. The method, kit, conjugate, use, or article of manufacture of any one of claims 117-129, wherein the conjugate has an Mwof about 286 kDa to 290 kDa.

131. The method, kit, conjugate, use, or article of manufacture of claim 130, wherein the conjugate has an Mwof about 287 kDa to about 289 kDa.

132. The method of any one of claims 1-46, 53, or 54, the kit of any one of claims 55, 102-108, or 110-116, the conjugate for use of any one of claims 56-66, the use of any one of claims 71-80, the article of manufacture of any one of claims 86-97, 99, or 100, wherein the portion of the conjugate lacking the Fabs has the structure of formula Id:(Id)359MF-366104678Attorney Docket No.: 146392070440and has a weight average molecular weight (Mw) of about 1000 to about 10,000 Da.

133. The method, kit, conjugate, use, or article of manufacture of claim 132, wherein the portion of the conjugate lacking the Fabs has an Mwof about 1675 to about 10,000 Da.

134. The method, kit, conjugate, use, or article of manufacture of claim 132, wherein the portion of the conjugate lacking the Fabs has an Mwof about 5400 to about 6600 Da.

135. The method, kit, conjugate, use, or article of manufacture of any one of claims 132-134, wherein the conjugate has an Mwof about 283 kDa to 293 kDa.

136. The method, kit, conjugate, use, or article of manufacture of any one of claims 135, wherein the conjugate has an Mwof about 286 kDa to 290 kDa.

137. The method, kit, conjugate, use, or article of manufacture of claim 136, wherein the conjugate has an Mwof about 287 kDa to about 289 kDa.

138. The method, kit, conjugate, use, or article of manufacture of any one of claims 117-137, wherein the conjugate is in a composition comprising a pharmaceutically acceptable carrier.360MF-366104678

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