Personalized treatment of ophthalmologic diseases

Abstract

This invention relates to antibodies that bind to VEGF and ANG2 for the treatment of ocular vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy, specifically diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO).

Description

Personalized treatment of eye diseases The present invention relates to antibodies that bind to VEGF and ANG2 for use in treating ocular vascular diseases, such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy, specifically diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO). Ocular vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), and diabetic retinopathy (specifically diabetic macular edema (DME)) are serious conditions that often lead to vision loss and blindness. Neovascular age-related macular degeneration (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD) is a late AMD form that causes rapid and severe vision loss and remains the leading cause of visual impairment in the elderly (Bourne et al., Lancet Glob Health 2013; 1: e339-49; Wong et al., Lancet Glob Health 2014; 2: e106-16). Several biochemical and biological processes such as angiogenesis, inflammation, and oxidative stress are known to play a role in the pathogenesis of nAMD, which is characterized by abnormal proliferation of choroidal capillaries that penetrate Bruch's membrane and transfer to or through the retinal pigment epithelium. If left untreated, CNV leaks fluid, lipids, and blood into the outer retina, causing severe, irreversible central vision loss. Before anti-vascular endothelial growth factor (anti-VEGF) agents, laser photocoagulation and photodynamic therapy using verteporfin were the standard of care and were shown to stabilize vision. Although such treatments remain a therapeutic option for selected patients, nAMD treatment has been significantly improved by the introduction of biomolecules that target VEGF-A, a key factor in pathological angiogenesis (Brown et al., N Engl J Med 2006;355:1432-44; Rosenfeld et al., N Engl J Med 2006;355:1419-31; Heier et al., Ophthalmology 2012;119:2537-48). Since the initial approval of Lucentis® (ranibizumab) in 2006, the impressive benefits of anti-VEGF therapy and its ability to restore vision have been widely recognized (American Academy of Ophthalmology 2015). A key challenge with currently available anti-VEGF therapies is the need for frequent and long-term dosing to maintain visual acuity gains (Heier et al., Ophthalmology 2012;119:2537-48; the Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] Research Group 2016 Ophthalmology 2016;123:1751-61). Real-world data suggest that many patients with nAMD do not receive treatment at the optimal frequency, and this undertreatment in clinical practice is associated with lower visual acuity (VA) gains compared to those observed in controlled clinical trials (Cohen et al., Retina 2013;33:474-81; Finger et al., Acta Ophthalmol 2013;91:540-6; Holz et al., Br J Ophthalmol 2015;99:220-6; Rao et al., Ophthalmology 2018;125:522-28). The undertreatment of nAMD in clinical practice reflects the burden of frequent therapy on patients, caregivers, and the healthcare system (Gohil et al., PLoS One 2015;10:e0129361; Prenner et al., Am J Ophthalmol 2015;160:725-31; Varano et al., Clin Ophthalmol 2015;9:2243-50; CATT Research Group et al., Ophthalmology 2016;123:1751-61; Vukicevic et al., Eye 2016;30:413-21). Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), may occur at any stage of the underlying disease of the retinal microvasculature (Fong et al., Diabetes Care 2004; 27: 2540-53). As the underlying DR deteriorates from non-proliferative DR (NPDR) to proliferative DR (PDR), the frequency of DME increases (Henricsson et al., Acta Ophthalmol. Scand. 1999: 77: 218-223; Johnson Am J Ophthalmol 2009; 147: 11-21). DME is the most common cause of moderate and severe visual impairment in patients with DR (Ciulla et al., Diabetes Care 2003;26:2653-64; Davidson et al., Endocrine 2007;32:107-16; Leasher et al., Diabetes Care 2016;39:1643-9) and, if left untreated, can lead to a visual acuity (VA) loss of 10 or more letters within 2 years in approximately 50% of patients (Ferris and Patz Surv Ophthamol 1984;28 Suppl:452-61; Diabetes Care 2003;26:2653-64 et al., 2003). DME affects approximately 14% of patients with diabetes and can be found in patients with both type 1 and type 2 diabetes (Girach and Lund-Andersen Int J Clin Practice 2007;61:88-97). In 2013, the number of people with diabetes worldwide was approximately 382 million, and it is estimated that this number will increase to 592 million by 2035 (International Diabetes Federation 2013). With advances in imaging technology, DME is now often diagnosed by optical coherence tomography (OCT) rather than by the traditional Early Treatment Diabetic Retinopathy Study (ETDRS) ophthalmoscopy-based criteria. At the molecular level, DME is the result of vascular endothelial growth factor-A (VEGF-A)-mediated increased vascular permeability and loss of outer membrane cells, resulting from hypoxia-induced release of proangiogenic, hyperpermeable, and proinflammatory mediators (Antonetti et al., Semin Ophthalmol 1999;14:240-8). VEGF also upregulates the homeostatic factor angiopoietin-2 (Ang-2), which acts as an antagonist of the Tie2 receptor tyrosine kinase on endothelial cells, counteracting vascular stability maintained by Ang-1-dependent Tie2 activation. Consequently, Ang-2 acts as a vascular destabilizing factor, rendering vascular structure more elastic and susceptible to endothelial barrier disruption and sprouting. Excessive levels of Ang-2 and VEGF in retinal tissue contribute to vascular instability, vascular leakage, and neovascularization. Ang-2 is also involved in inflammatory pathways, such as lymphocyte recruitment. Overall, both VEGF-A and Ang-2 are recognized as key factors mediating the pathogenesis of diabetic eye disease (Aiello et al., N Engl J Med 1994;331:1480-7; Davis et al., Cell 1996;87:1161-9; Maisonpierre et al., Science 1997;277:55-60; Gardner et al., Surv Ophthalmol 2002;47(Suppl 2):S253-62; Joussen et al., Am J Path 2002;160:501-9; Fiedler et al., J Biol Chem 2003;278:1721-7). Although macular laser therapy remains the standard of care (SOC) for treating DME, the development of anti-VEGF drug therapies over the past decade has led to significant improvements in visual outcomes for patients with DME. Currently available anti-VEGF therapies for DME include ranibizumab and aflibercept. Other available approved options for treating DME include periocular or intravitreal (IVT) steroids and steroid implants. Despite the strong efficacy achieved with anti-VEGF therapy in DME, in the real world, a large proportion of patients do not experience clinically meaningful vision improvement. Frequent IVT administration is required to achieve, and in some cases maintain over extended periods of time, the observed benefits of early DME treatment. The current system of care for administering anti-VEGF injections requires patients to undergo frequent clinical examinations and IVT injections. This places a significant burden on patients, caregivers, treating physicians, and the healthcare system. Large phase III trials of anti-VEGF agents in diabetic eye mesenchymal encephalopathy (DME) have demonstrated that the number of injections required to maintain visual acuity after the first year of treatment can be reduced (Diabetic Retinopathy Clinical Research Network et al., Ophthalmology 2010;117:1064-77. Epub 2010 Apr 28; Schmidt-Erfurth et al., Ophthalmology 2014;121:193-201; Elman et al., Ophthalmology 2015;122:375-81). However, in the absence of validated predictive biomarkers for treatment frequency, the standard anti-VEGF approach for DME still relies on frequent monitoring visits and places a significant burden on patients and healthcare providers. Furthermore, anti-VEGF monotherapy does not fully address other pathways that contribute to the progression of diabetic eye disease, including inflammation and outer membrane cell instability. New treatments that target additional pathways and allow for a reduced burden of IVT injections are needed to address the high unmet medical need in DME. According to one aspect of the present invention, a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for treating a patient suffering from an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME) is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) on a personalized treatment interval (PTI) regimen, wherein treatment of the patient suffering from the ocular vascular disease selected from nAMD and DME includes a dosing schedule with extended dosing intervals in the absence of stable disease or shortened intervals in the presence of disease activity. In this way, the patient is optimally treated, thereby ensuring improvement and / or maintenance of their vision while reducing unnecessary treatment burden. According to another aspect of the present invention, methods, uses, bispecific antibodies (for use), medicaments, or pharmaceutical formulations for treating patients with a specific neovascular AMD (nAMD) (also known as wet AMD (wAMD)) are provided, comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) on a personalized treatment interval (PTI) schedule, wherein treatment of patients with nAMD includes a dosing schedule with extended dosing intervals in the absence of stable disease or shortened intervals in the presence of disease activity. In this way, patients are optimally treated, thereby ensuring improvement and / or maintenance of their vision while reducing unnecessary treatment burden. According to one aspect of the present invention, a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for treating a patient suffering from AMD is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein treatment of the patient suffering from AMD comprises a dosing schedule after initiation of treatment with extended dosing intervals in the absence of stable disease or shortened dosing intervals in the presence of active disease. One embodiment is such a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for treating a patient suffering from neovascular AMD (nAMD), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, wherein a) the patient is first treated four times with the bispecific VEGF / ANG2 antibody at a every four weeks (Q4W) dosing interval; b) disease activity is assessed at weeks 20 and 24, wherein the disease activity is determined to meet one of the following criteria: i) an increase in central subfield thickness (CST) of >50 μm compared to the mean CST values ​​of the two previous scheduled visits, the week 20 assessment being for the week 12 and week 16 visits and the week 24 assessment being for the week 16 and week 20 visits, or ii) ≥ 75 μm increase in CST compared to the lowest CST value recorded at either of the two prior scheduled visits; iii) ≥ 5-letter decrease in best-corrected visual acuity (BCVA) compared to the mean BCVA value at the two prior scheduled visits due to nAMD disease activity, iv) ≥ 10-letter decrease in BCVA compared to the highest BCVA value recorded at either of the two prior scheduled visits due to nAMD disease activity, or v) development of new macular hemorrhage due to nAMD activity c) Patients then i) Patients who meet disease activity criteria at Week 20 will be treated at an every 8-week (Q8W) dosing interval beginning at Week 20 (with the first Q8W dose at Week 20); ii) Patients who meet disease activity criteria at Week 24 will be treated at an every 12-week (Q12W) dosing interval beginning at Week 24 (with the first Q12W dose at Week 24); and iii) Patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated at a Q16W dosing interval starting at Week 28 (with the first Q16W dose at Week 28). In one embodiment, after Week 60, the personalized treatment interval will be extended, shortened, or maintained, where a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the two most recent study drug dosing visits, where stability is defined as a change in CST of less than 30 µm and no increase in CST of ≥ 50 µm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement, iii) no new macular hemorrhage; b) the interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria, or one criterion includes a new macular hemorrhage, is met: i) CST has increased by ≥ 50 µm compared to the average of the two most recent study drug dosing visits; µm, or a CST increase of ≥ 75 µm compared to the lowest dosing visit measurement, ii) a decrease in BCVA of ≥ 5 letters compared to the average of the two most recent dosing visits, or a decrease in BCVA of ≥ 10 letters compared to the highest dosing visit measurement, iii) a new macular hemorrhage. According to another aspect of the present invention, methods, uses, bispecific antibodies (for use), medicaments, or pharmaceutical formulations for treating patients suffering from diabetic retinopathy, specifically diabetic macular edema (DME), are provided. The methods comprise administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) on a personalized treatment interval (PTI) schedule, wherein treatment of patients suffering from DME includes a dosing schedule that extends the dosing interval in the absence of stable disease or shortens the dosing interval in the presence of active disease. In this way, patients are optimally treated, thereby ensuring improvement and / or maintenance of their vision while reducing unnecessary treatment burden. One embodiment is such a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for treating a patient suffering from diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, wherein a) the patient is initially treated with the bispecific VEGF / ANG2 antibody at a dosing interval of every 4 weeks (Q4W) until the central retinal thickness (CST) of the macula meets a predetermined reference CST threshold (CST <325 μm for Spectralis SD-OCT or CST <315 μm for Cirrus SD-OCT or Topcon SD-OCT) as measured at or after week 12; b) the dosing interval is then increased by 4 weeks to an initial dosing interval of every 8 weeks (Q8W); c) From this point on, the dosing interval is extended, shortened, or maintained based on assessments performed at the dosing visits based on the relative changes in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) the interval is maintained if: - the CST decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters; or - the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened by 8 weeks if the CST value increases by >10% with an associated BCVA decrease of ≥10 letters; wherein the respective reference central macular retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive dosing visits, and such values ​​are obtained within 30 µm, such that the CST value obtained at the subsequent visit serves as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit. In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. According to another aspect of the present invention, a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for treating a patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion is provided, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) on a personalized treatment interval (PTI) regimen, wherein the treatment of the patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion includes a dosing schedule that extends the dosing interval in the absence of stable disease or shortens the dosing interval in the presence of active disease. In this way, the patient is optimally treated, thereby ensuring improvement and / or maintenance of their vision while reducing unnecessary treatment burden. One embodiment is such a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for treating a patient suffering from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, wherein a) the patient is initially treated with the bispecific VEGF / ANG2 antibody at a every 4 weeks (Q4W) dosing interval from day 1 to week 20; b) starting at week 24, the patient receives the bispecific VEGF / ANG2 antibody at a Q4W frequency until the central retinal thickness (CST) of the macula meets a predetermined reference CST threshold; c) from this point on, the dosing interval is extended, shortened or maintained based on assessments performed at the dosing visits, the assessments being based on the relative changes in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) The interval is extended to 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria is met: the CST value decreases by > 10%; or the CST value decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened to 4 weeks if any of the following criteria is met: the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters, or the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; or the CST value increases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened to Q4W if the CST value increases by > 10% with an associated BCVA decrease of ≥ 10 letters, wherein the respective reference central macular retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive dosing visits, and such values ​​are obtained to within 30 μm, such that the CST value obtained at the subsequent visit will serve as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit. In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. In one embodiment of the present invention, the bispecific antibody that binds to human VEGF and human ANG-2 is a bispecific, bivalent anti-VEGF / ANG-2 antibody, comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6. The invention further comprises a bispecific antibody comprising a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat). In one embodiment of the invention, the patient suffering from an ocular vascular disease has not been previously treated with anti-VEGF therapy (eg, monotherapy) (is treatment naive). In one embodiment of the invention, the patient suffering from an ocular vascular disease has been previously treated with anti-VEGF therapy (eg, monotherapy). In one embodiment of the present invention, the disclosed bispecific antibodies are administered according to the assays performed by the software tool. Methods, uses, bispecific antibodies (for use), medicaments, or pharmaceutical formulations for treating an ocular vascular disease selected from nAMD and DME comprise sequential administration of an initial dose ("treatment initiation"). In some embodiments, the initial dose may vary, for example, from once every 3 months to once every 7 months; in one embodiment, treatment initiation comprises administration once every 3 to 4 months, in one embodiment, treatment initiation comprises administration once every 4 to 5 months; in one embodiment, treatment initiation comprises administration once every 4 to 6 months; in one embodiment, treatment initiation comprises administration at least once every 4 months; in one embodiment, treatment initiation comprises administration once every 5 to 7 months, in one embodiment, treatment initiation comprises administration once every 6 months. In one embodiment of the invention, the bispecific antibody, drug, or pharmaceutical formulation is administered at a dose of about 5 to 7 mg (at each treatment). In one embodiment, the bispecific antibody is administered at a dose of 6 mg + / - 10% (at each treatment). In one embodiment, the bispecific antibody is administered at a dose of about 6 mg (at each treatment) (in one embodiment, at a dose of 6 mg (at each treatment)). In one embodiment of the invention, the bispecific antibody, drug, or pharmaceutical formulation is administered at a bispecific antibody concentration of about 120 mg / ml (+ / - 12 mg / ml). Macular degeneration is a medical condition found primarily in older adults in which the central lining of the eye, an area called the macula of the retina, thins, atrophies, and in some cases bleeds. This can lead to a loss of central vision, which causes an inability to see fine details, read, or recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of 50. Although some macular dystrophies that affect younger individuals are sometimes referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD). As used herein, "age-related macular degeneration (AMD)" refers to a serious eye condition when the small central part of the retina called the macula deteriorates. AMD includes wet AMD and neovascular AMD. The wet form of AMD (wet AMD, wAMD, or also known as neovascular AMD, nAMD) is characterized by the growth of abnormal blood vessels from the choroid under the macula. This is called choroidal neovascularization. These blood vessels leak blood and fluid (under the retina and) into the retina, resulting in visual distortion (elevation of the retina and) making straight lines look wavy, as well as blind spots and loss of central vision. These abnormal blood vessels eventually scar, resulting in permanent loss of central vision. Symptoms of AMD include a dark, blurred area in the center of vision; and reduced or altered color perception. AMD can be detected during a routine eye exam. One of the most common early signs of macular degeneration is drusen, which are tiny yellow deposits present under the retina and pigment aggregation. The late stage AMD that causes profound vision loss has two forms: dry and wet.Central map atrophy, i.e. the late stage AMD of dry form is caused by atrophy to the retinal pigment epithelium below the retina, and it causes vision loss via the photoreceptor (rods and cones) in the central part of the eye.Although no treatment can be used for this condition, the vitamin supplements with high doses of antioxidants, lutein and zeaxanthin have been confirmed by the National Eye Institute (the National Eye Institute) and other institutions to slow down the progress of dry macular degeneration and improve vision in some patients. As used herein, "diabetic macular edema" (DME) refers to a serious eye condition that affects people with diabetes (type 1 or type 2). Macular edema occurs when blood vessels in the retina leak into the macula and fluid and protein deposits collect on or below the macula of the eye, causing it to thicken and swell (edema). As the macula is near the center of the retina at the back of the eyeball, the swelling can distort a person's central vision. The main symptoms of DME include, but are not limited to, blurred vision, floaters, loss of contrast, double vision, and ultimately loss of vision. The pathology of DME is characterized by the breakdown of the blood-inner retinal barrier that normally prevents fluid from moving in the retina, thereby allowing fluid to accumulate in the retinal tissue and there is retinal thickening. DME is currently diagnosed during an eye exam that consists of a vision test (which determines the smallest letter a person can read on a standardized chart), a dilated eye exam to check for signs of the disease, imaging tests (such as optical coherence tomography (OCT) or fluorescein angiography (FA) and pressure measurement), and instruments (which measure the pressure inside the eye). The following studies are also performed to determine treatment: optical coherence tomography (OCT), fluorescein angiography, and color stereo fundus photography. DME can be broadly characterized as two main categories: focal and diffuse. Focal DME is characterized by specific areas of separate and distinct leakage in the macula with adequate macular blood flow. Diffuse DME results from leakage throughout the capillary bed surrounding the macula, which results from the breakdown of the eye's internal blood-retinal barrier. In addition to focal and diffuse, DME is also classified based on clinical examination findings into clinically significant macular edema (CSME), non-CSME, and CSME with central involvement (CSME-CI), which involves the fovea. The present invention includes methods of treating the above-mentioned categories of DME. Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders and is associated with varying degrees of vision loss (Hayreh and Zimmerman 1994). After diabetic retinopathy (DR), RVO has been reported to be the second leading cause of blindness in patients with retinal vascular disease (Cugati S, Wang JJ, Rochtchina E et al., Arch Ophthalmol 2006; 124: 726-732; Klein R, Knudtson MD, Lee KE et al., Ophthalmology 2008; 115: 1859-1868; Rogers S, McIntosh RL, Cheung N et al., Ophthalmology 2010 Feb; 117: 313-9.e1; Yasuda M, Kiyohara Y, Arakawa S et al., Invest Ophtahlmol Vis Sci 2010; 51: 3205-3209). The main types of RVO include branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). The most common presenting symptom of RVO is a sudden, painless decrease in central vision due to macular edema. The main types of macular edema secondary to RVO include macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), and macular edema secondary to central retinal vein occlusion (CRVO). Less frequently, patients may present with a history of transient visual loss lasting from seconds to minutes, followed by complete recovery of vision. These symptoms may recur within days to weeks, followed by permanent vision loss. Metamorphopsia and visual field defects have also been described (Achiron A, Lagstein O, Glick M et al., Acta Ophthalmologica 2015;93:e649-53; Manabe K, Osaka R, Nakano Y et al., PLoS One 2017;12:e0186737). The pathogenesis of macular edema in these patients begins with an increase in intraluminal pressure due to vascular occlusion, which results in areas of decreased perfusion and ischemia. Ischemia induces upregulation and secretion of vascular endothelial growth factor (VEGF) (Boyd SR, Zachary I, Chakravarthy U et al., Arch Ophthalmol 2002;12:1644-1650; Noma H, Minamoto A, Funatsu H et al., Graefes Arch Clin Exp Ophthalmol 2006;244:309-315) and angiopoietin-2 (Ang-2), both of which are well-known pro-angiogenic and vascular hyperpermeability cytokines, with Ang-2 contributing additional pro-inflammatory and vascular destabilizing properties (Maisonpierre PC, Suri C, Jones PF et al., Science 1997;277:55-60; Hackett SF, Ozaki H, Strauss RW et al., J Cell Physiol 2000;184:275-284; Fiedler U, Reiss Y, Scharpfenecker M et al., Nat Med 2006;244:309-315). 2006;12:235-239. Epub 2006 Feb 5). Among all retinal vascular diseases, patients with RVO have been found to have the highest vitreous levels of both Ang-2 and VEGF (Aiello LP, Avery RL, Arrigg PG, et al., N Engl J Med 1994;331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288). In many patients, increased levels of Ang-2 and VEGF in retinal tissue lead to pathological changes in the retina and macular edema, which is accompanied by decreased vision. The hallmarks of RVO are a characteristic pattern of retinal hemorrhages, tortuosity, and dilated retinal veins throughout the affected retinal area (one quadrant in BRVO, two quadrants in HRVO, and the entire retina in CRVO). In more severe cases, patients may develop retinal ischemia with subsequent retinal neovascularization, hemorrhage, anterior segment neovascularization leading to rubeosis iridis or neovascular glaucoma, and some patients may develop optic disc edema. Although macular edema due to RVO and diabetic macular edema (DME) has different origins, they share a common pathophysiology. They are characterized by macular thickening due to fluid accumulation (caused by breakdown of the blood-retinal barrier) and pathological increases in retinal vascular permeability, which can lead to irreversible vision loss in both diseases. Anti-VEGF drug therapy is the current mainstay of treatment for macular edema due to RVO and has demonstrated efficacy in several pivotal randomized clinical studies, although macular lasers and intravitreal (IVT) steroids—particularly steroid implants—are also used in some cases. Although anti-VEGF is the most effective treatment for macular edema due to RVO, data from anti-VEGF clinical trials demonstrate that many patients do not achieve optimal best-corrected visual acuity (BCVA) and anatomical outcomes, and many require frequent, long-term injections to maintain gains achieved during initial intensive treatment. Furthermore, real-world data analyses suggest that many patients with RVO do not achieve the gains seen in clinical trials due to suboptimal injection frequency (Vaz-Pereira, S, Marques IP, Matias J, et al., Eur J Ophthalmol 2017;27:756-761; Wecker T, Ehlken C, Buhler A, et al., Br J Ophthalmol 2017;101:353-359; Jumper JM, Dugel PU, Chen S, et al., Clin Ophthalmol 2018;12:621-629). Data suggest that many patients with macular edema due to BRVO and many patients with macular edema due to CRVO require close monitoring and longer periods of treatment and that more durable and effective treatment options are needed (Bhisitkul RB, Campochiaro PA, Shapiro H, et al., Ophthalmology 2013;120:1057-1063; Scott IU, Neal NL, VanVeldhuisen, et al., JAMA Ophthalmol 2019;E1-E10). Nonclinical studies have shown that Ang-2 and VEGF act synergistically to regulate vascular structure and increase retinal endothelial cell permeability in vitro. Simultaneous inhibition of Ang-2 and VEGF with the bispecific monoclonal antibody flucipirimumab resulted in greater reductions in leakage and severity of choroidal neovascularization (CNV) lesions in a laser-induced CNV model in non-human primates compared to molar equivalents of either anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a mouse model of spontaneous CNV demonstrated that dual inhibition of Ang-2 and VEGF consistently outperformed monotherapy inhibition of either target alone in terms of reductions in vessel growth, leakage, edema, leukocyte infiltration, and loss of the photoreceptor organ (Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288). In addition, aqueous humor and vitreous concentrations of both Ang-2 and VEGF were shown to be upregulated in patients with neovascular age-related macular degeneration (nAMD), DR, and RVO (Tong JP, Chan WM, Liu DT, et al., Am J Ophthalmol 2006;141:456-462; Penn JS, Madan A, Caldwell RB, et al., Prog Retin Eye Res 2008;27:331-371.; Kinnunen K, Puustjärvi T, Teräsvirta M, et al., Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288; Ng DS, Yip YW, Bakthavatsalam M, et al., Sci Rep 2017;7:45081). Therefore, simultaneous neutralization of both Ang-2 and VEGF, compared with anti-VEGF therapy alone, may further normalize pathological ocular vasculature. Data from full-scale Phase II studies in DME and nAMD (see below) also support the hypothesis that targeting Ang-2 has the potential to prolong the durability of efficacy beyond anti-VEGF therapy alone in diseases affecting retinal vasculature. Fluximab has been studied for the treatment of nAMD and DME in two Phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME). Four global Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) for DME, and GR40306 (TENAYA) and GR40844 (LUCERNE) for nAMD. Based on the mechanism of action of fluvicipizumab, data from nonclinical and clinical trials, and the pathophysiology of macular edema due to RVO, it was hypothesized that fluvicipizumab may cause stabilization of pathological ocular vascular structures and improve the visual and anatomical outcomes of RVO compared to anti-VEGF monotherapy. Macular edema secondary to / due to RVO is the most common retinal vascular disease (Aiello LP, Avery RL, Arrigg PG, et al., N Engl J Med 1994;331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288). The efficacy of Ang-2 and VEGF inhibition in nonclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288) and data from phase I and II studies of fluvicipizumab in patients with nAMD and DME provide evidence of efficacy against pathological pathways common to all three retinal vascular diseases, nAMD, DME / DR, and macular edema due to RVO (Phase I study: BP28936 in nAMD; Phase II studies: AVENUE in nAMD, STAIRWAY in nAMD, and BOULEVARD in DME). Because the pathophysiology between DME and macular edema due to RVO is similar, data from the Phase II BOULEVARD study are reported here. Although the triggers of macular edema in diabetic and RVO patients are different, the downstream pathophysiology of hypoxia-driven macular edema and subsequent visual loss is similar and driven by the same pro-angiogenic, pro-inflammatory, vascular instability, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6). The BOULEVARD study provides basic evidence of the positive benefit-risk profile of using 6-mg IVF flucipirimumab injections in patients with DME and supports further evaluation of flucipirimumab in a Phase III DME study. The study met its primary efficacy endpoint, demonstrating a statistically significant improvement in the mean change from baseline BCVA at Week 24 in patients not previously treated with anti-VEGF therapy, treated with 6 mg flucipirimumab compared to 0.3 mg ranibizumab. Best corrected visual acuity (BCVA) is determined using a method adapted according to the 4-meter Early Treatment Diabetic Retinopathy Study (ETDRS) protocol (using an Early Treatment Diabetic Retinopathy Study (ETDRS) similar chart) and generating individual letter scores. In one embodiment, the BCVA determination in such methods, uses, bispecific antibodies (for use), medicaments, or pharmaceutical formulations is based on an Early Treatment Diabetic Retinopathy Study (ETDRS) protocol-adapted visual acuity chart and is assessed at a starting distance of 4 meters. Disease activity is measured, for example, by a decrease in BCVA / ETDR letter scores and / or by macular thickening, for example, by spectral domain optical coherence tomography (SD-OCT) involving the center of the macula as central retinal thickness (CST), also known as central subfoveal thickness. In a preferred embodiment, central retinal thickness (CST) is measured using spectral domain optical coherence tomography (SD-OCT). In a preferred embodiment, CST is measured using Spectralis TM The device is measured by spectral domain optical coherence tomography (SD-OCT); in a preferred embodiment, CST is measured by Cirrus TM The device is measured by spectral domain optical coherence tomography (SD-OCT); in one embodiment, CST is measured by Topcon TM The device is measured by spectral domain optical coherence tomography (SD-OCT); in one embodiment, CST is measured using Optovue TMThe device is measured by spectral domain optical coherence tomography (SD-OCT). As used herein, the term "patient suffering from..." refers to a human who exhibits one or more symptoms or indications of an ocular vascular disease as described herein and / or has been diagnosed with an ocular vascular disease as described herein. The term "patient suffering from..." may also include, for example, individuals who, prior to treatment, exhibit (or have exhibited) one or more indications of a vascular eye disease, such as, for example, retinal angiogenesis, neovascularization, vascular leakage, retinal thickening in the center of the fovea, hard yellow discharge in the center of the fovea with adjacent retinal thickening, and retinal thickening of at least one disk area (any portion of which is within one disk diameter of the center of the fovea), blurred vision, floaters, loss of contrast, diplopia, and ultimately loss of vision. As used herein, the term "patient suffering from" an ocular vascular disease such as nAMD or DME may include a subset of a population that is more susceptible to nAMD or DME or that may display elevated levels of nAMD-related or DME-related biomarkers. For example, a "patient suffering from DME" may include an individual who has had diabetes for more than 10 years, has frequently high blood glucose levels, or has high fasting blood glucose levels. In certain embodiments, the term "patient suffering from DME" includes an individual who has or is diagnosed with diabetes prior to or at the time of administration of the bispecific anti-VEGF / ANG2 antibody. In certain embodiments, the term "patient suffering from nAMD" includes an individual who is over 50 years old prior to or at the time of administration of the anti-VEGF / ANG2 antibody. In some embodiments, the term "patient suffering from..." includes an individual who is a smoker or an individual who has high blood pressure or high cholesterol. As used herein, the term "patient suffering from" an ocular vascular disease, such as macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO), may include a subset of a population that is more susceptible to macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to hemiretinal vein occlusion (HRVO), or macular edema secondary to central retinal vein occlusion (CRVO) or may exhibit elevated levels of RVO-associated biomarkers. For example, a "patient suffering from RVO or macular edema secondary to RVO" may include individuals with increased levels of VEGF, ANG2, or IL-6. In some embodiments, the term "patient suffering from..." includes individuals who are smokers or individuals with high blood pressure or high cholesterol. The present invention includes methods or bispecific antibodies (for use), medicaments, or pharmaceutical formulations for treating, preventing, or reducing the severity of ocular vascular diseases, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-VEGF / ANG2 antibody (or a medicament or pharmaceutical formulation comprising a bispecific anti-VEGF / ANG2 antibody), wherein the bispecific antibody, medicament, or pharmaceutical formulation comprising such a bispecific anti-VEGF / ANG2 antibody is administered to the subject (intravitreally) in multiple doses, e.g., as part of a specific therapeutic dosing regimen. One embodiment of the invention is a method of treatment, use, bispecific antibody (for use), medicament or pharmaceutical formulation as described herein, wherein the patient suffering from an ocular vascular disease has not been previously treated with anti-VEGF therapy (e.g., monotherapy) (is treatment naive). One embodiment of the invention is a method of treatment, a use, a bispecific antibody (for use), a medicament or a pharmaceutical formulation as described herein, wherein the patient suffering from an ocular vascular disease has previously been treated with an anti-VEGF therapy (e.g., monotherapy, such as with ranibizumab, aflibercept or brolocizumab). One embodiment of the present invention is a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for treating a patient suffering from neovascular AMD (nAMD), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, wherein a) the patient is initially treated four times with the bispecific VEGF / ANG2 antibody at a every four weeks (Q4W) dosing interval; b) disease activity is assessed at Week 20 and Week 24, wherein the disease activity is determined to meet one of the following criteria: i) an increase in central macular retinal thickness (CST) of >50 μm compared to the mean CST value of the two previous scheduled visits, the Week 20 assessment being for the Week 12 and Week 16 visits and the Week 24 assessment being for the Week 16 and Week 20 visits, or ii) an increase in CST of ≥75 μm compared to the lowest CST value recorded at either of the two previous scheduled visits. μm; iii) BCVA loss of ≥ 5 letters compared to the mean best-corrected visual acuity (BCVA) value of the two prior scheduled visits due to nAMD disease activity, iv) BCVA loss of ≥ 10 letters compared to the highest BCVA value recorded at either of the two prior scheduled visits due to nAMD disease activity, or v) development of new macular hemorrhage due to nAMD activity c) Patients then i) patients who meet disease activity criteria at Week 20 will be treated with a Q8W dosing interval beginning at Week 20 (with the first Q8W dose at Week 20); ii) patients who meet disease activity criteria at Week 24 will be treated with a Q12W dosing interval beginning at Week 24 (with the first Q12W dose at Week 24); and iii) patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval beginning at Week 28 (with the first Q16W dose at Week 28). In one embodiment, after Week 60, the personalized treatment interval will be extended, shortened, or maintained, wherein a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the two most recent study drug dosing visits, where stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥ 50 μm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement, iii) no new macular hemorrhage; b) the interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria, or one criterion includes a new macular hemorrhage, is met: i) CST has increased by ≥ 50 μm compared to the average of the two most recent study drug dosing visits; µm, or a CST increase of ≥ 75 µm compared to the lowest dosing visit measurement, ii) a decrease in BCVA of ≥ 5 letters compared to the average of the two most recent dosing visits, or a decrease in BCVA of ≥ 10 letters compared to the highest dosing visit measurement, iii) a new macular hemorrhage. In one embodiment, disease activity assessments prior to the personalized treatment interval will be at the Week 16 and Week 20 visits, or at the Week 24 and Week 28 visits. In one embodiment, depending on disease activity, further extended, shortened or maintained personalized treatment intervals will be initiated at different time points, for example between weeks 50 and 70, for example after week 52 or after week 65. Another embodiment of the present invention is a method, use, bispecific antibody (for use), medicament, or pharmaceutical formulation for treating a patient suffering from diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, wherein a) the patient is initially treated with the bispecific VEGF / ANG2 antibody at a every 4 weeks (Q4W) dosing interval until the central retinal thickness (CST) of the macula meets a predetermined reference CST threshold (CST <325 µm for Spectralis SD-OCT or CST <315 µm for Cirrus SD-OCT or Topcon SD-OCT) as measured at or after week 12; b) the dosing interval is then increased by 4 weeks to an initial Q8W dosing interval; c) From this point on, the dosing interval is extended, shortened, or maintained based on assessments performed at the dosing visits based on the relative changes in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) the interval is maintained if: - the CST decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters; or - the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened by 8 weeks if the CST value increases by >10% with an associated BCVA decrease of ≥10 letters; wherein the respective reference central macular retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive dosing visits, and such values ​​are obtained within 30 µm, such that the CST value obtained at the subsequent visit serves as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit. In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. Another embodiment of the present invention is a method, use, bispecific antibody (for use), medicament or pharmaceutical formulation for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion, or a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI) wherein a) the patient is first treated with the bispecific VEGF / ANG2 antibody at a dosing interval of every four weeks (Q4W) from day 1 to week 20; b) starting from week 24, the patient receives the bispecific VEGF / ANG2 antibody at a frequency of Q4W until the central retinal thickness (CST) of the macula meets a predetermined reference CST threshold (CST <325 μm for Spectralis SD-OCT or <400 μm for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured at Week 24 or later); c) beginning at this point, extend, shorten, or maintain the dosing interval based on assessments performed at the dosing visits based on the relative change in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; where i) the interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria is met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10% with an associated decrease in BCVA of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 20% without an associated decrease in BCVA of ≥ 5 letters; iii) the interval is shortened by 4 weeks if any of the following criteria is met: an increase in the CST value of > 10% and ≤ 20% with an associated decrease in BCVA of ≥ 5 to < 5 letters iv) the interval is shortened to Q4W if the CST value increases by >10% with an associated BCVA decrease of ≥10 letters, or the CST value increases by >20% without an associated BCVA decrease of ≥10 letters; or the CST value increases by ≤10% with an associated BCVA decrease of ≥10 letters; iv) the interval is shortened to Q4W if the CST value increases by >10% with an associated BCVA decrease of ≥10 letters, wherein the respective reference central retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive dosing visits, and such values ​​are obtained within 30 µm, such that the CST value obtained at the subsequent visit serves as the new reference CST;and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit.; In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. As used herein, "antibody" refers to a binding protein that comprises an antigen binding site. As used herein, the term "binding site" or "antigen binding site" refers to one or more regions of an antibody molecule to which a ligand actually binds. The term "antigen binding site" comprises an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) (VH / VL pair). Antibody specificity refers to the selective recognition of a specific antigenic determinant by an antibody. For example, natural antibodies are monospecific. According to the present invention, a "bispecific antibody" is an antibody with two different antigen binding specificities. The antibody of the present invention is specific for two different antigens, VEGF as the first antigen and ANG-2 as the second antigen. As used herein, the term "monospecific" antibody refers to an antibody that has one or more binding sites that each bind to the same antigenic determinant on the same antigen. As used in this application, the term "valent" refers to the presence of a specified number of binding sites in an antibody molecule. Thus, the terms "bivalent," "tetravalent," and "hexavalent" refer to the presence of two, four, and six binding sites, respectively, in an antibody molecule. The bispecific antibodies according to the present invention are preferably bivalent. As used herein, the terms "bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2)", "bispecific anti-VEGF / ANG2 antibody" and "bispecific <VEGF / ANG2> antibody" are interchangeable and refer to an antibody that has at least two different antigen-binding sites, the first of which binds to VEGF and the second to ANG2. Bispecific anti-VEGF / ANG2 antibodies are described, for example, in WO2010040508, WO2011 / 117329, WO2012 / 131078, WO2015 / 083978, WO2017 / 197199, and WO2014 / 009465. WO2014 / 009465 describes bispecific anti-VEGF / ANG2 antibodies designed, inter alia, for the treatment of ocular vascular diseases. The bispecific anti-VEGF / ANG2 antibodies of WO2014 / 009465 (incorporated herein in their entirety) are particularly suitable for the treatment and treatment scheduling of ocular vascular diseases as described herein. In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6. The invention further comprises a bispecific antibody comprising a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat). In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are bivalent. In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are characterized in that i) the first antigen-binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain, VH, and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain, VL, and ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain, VH, and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain, VL. In one aspect of the invention, such bispecific, bivalent antibodies according to the invention are characterized in that they comprise a) the heavy and light chains of a first full-length antibody that specifically binds to VEGF; b) a modified heavy chain and a modified light chain of a second full-length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 are mutually replaced. This bispecific, bivalent antibody format, which specifically binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), is described in WO 2009 / 080253 (including a knob-into-hole modified CH3 domain). Antibodies based on this bispecific, bivalent antibody format are named CrossMAb. In one embodiment, such bispecific, bivalent anti-VEGF / ANG2 antibodies are characterized in comprising a) the amino acid sequence of SEQ ID NO: 17 as the heavy chain of the first full-length antibody, and the amino acid sequence of SEQ ID NO: 18 as the light chain of the first full-length antibody, and b) the amino acid sequence of SEQ ID NO: 19 as the modified heavy chain of the second full-length antibody, and the amino acid sequence of SEQ ID NO: 20 as the modified light chain of the second full-length antibody. In one embodiment, such bispecific, bivalent anti-VEGF / ANG2 antibody is characterized by comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. In a preferred embodiment, the bispecific, bivalent anti-VEGF / ANG2 antibody is flucipirimumab. Therefore, one embodiment of the present invention is a bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, characterized by comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. In a preferred embodiment, the bispecific, bivalent anti-VEGF / ANG-2 antibody is flucipirimumab. In one embodiment, the CH3 domains of the bispecific, bivalent antibodies according to the present invention are modified using the "knob-and-hole" technique, which is described in detail, for example, in WO 96 / 027011, Ridgway JB et al., Protein Eng 9 (1996) 617-621; and Merchant, AM et al., Nat Biotechnol 16 (1998) 677-681. In this approach, the interaction surfaces of the two CH3 domains are altered to enhance heterodimerization of the two heavy chains containing these two CH3 domains. Each of the two CH3 domains (of the two heavy chains) can be a "knob" and the other a "hole." The introduction of disulfide bridges stabilizes the heterodimer (Merchant, AM et al., Nature Biotech 16 (1998) 677-681; Atwell, S. et al., J. Mol. Biol. 270 (1997) 26-35) and increases production. In a preferred aspect of the invention, the bispecific anti-VEGF / ANG2 antibody according to the invention is characterized in that the CH3 domain of one heavy chain and the CH3 domain of the other heavy chain each meet at an interface comprising the original interface between antibody CH3 domains, wherein the interface is altered to facilitate the formation of a bispecific antibody, wherein the alteration is characterized in that: a) the CH3 domain of one heavy chain is altered such that, within the original interface, the CH3 domain of one heavy chain meets the original interface of the CH3 domain of the other heavy chain in the bispecific antibody, amino acid residues are replaced with amino acid residues having a larger side chain volume, thereby generating a protrusion within the interface of the CH3 domains of one heavy chain, wherein the protrusion can be positioned in a cavity within the interface of the CH3 domains of the other heavy chain, and b) the CH3 domain of the other heavy chain is altered, The native interface amino acid residues of the first CH3 domain in the bispecific antibody that are encountered within the native interface of the second CH3 domain are replaced by amino acid residues with smaller side chain volumes, thereby generating a cavity within the interface of the second CH3 domain, into which the protrusion within the interface of the first CH3 domain can be positioned. Thus, the bispecific anti-VEGF / ANG2 antibodies for use as described herein are preferably characterized in that a) the CH3 domains of the heavy chains of the full length antibody and b) the CH3 domains of the heavy chains of the full length antibody each meet at an interface that comprises a change in the original interface between the antibody CH3 domains; wherein i) in the CH3 domain of one heavy chain, amino acid residues are replaced with amino acid residues having a larger side chain volume, thereby generating a protrusion within the interface of the CH3 domains of one heavy chain, which protrusion can be positioned in a cavity within the interface of the CH3 domains of the other heavy chain, and wherein ii) in the CH3 domain of the other heavy chain, amino acid residues are replaced with amino acid residues having a smaller side chain volume, thereby generating a cavity within the interface of the second CH3 domain, within which the protrusion within the interface of the first CH3 domain can be positioned. Preferably, the amino acid residue with a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). Preferably, the amino acid residue with a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), and valine (V). In one aspect of the present invention, the two CH3 domains are further modified by introducing cysteine ​​(C) as an amino acid in the corresponding position of each CH3 domain, so that a disulfide bridge can be formed between the two CH3 domains. In one embodiment, the bispecific antibody comprises a T366W mutation in the CH3 domain of the "knob chain" and T366S, L368A, and Y407V mutations in the CH3 domain of the "hole chain." Additional interchain disulfide bridges between the CH3 domains can also be used, for example, by introducing an S354C mutation into one CH3 domain and a Y349C mutation into the other CH3 domain (Merchant, AM et al., Nature Biotech 16 (1998) 677-681). In another preferred embodiment, the bispecific antibody comprises S354C and T366W mutations in one of the two CH3 domains and Y349C, T366S, L368A, Y407V mutations in the other of the two CH3 domains. In another preferred embodiment, the bispecific antibody comprises Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains (with an additional Y349C or S354C mutation in one CH3 domain and an additional S354C or Y349C mutation in the other CH3 domain, thereby forming interchain disulfide bridges) (numbering throughout according to the EU index of Kabat (Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Other techniques for CH3 modification to enhance heterodimerization are contemplated as alternatives to the present invention and are described, for example, in WO 96 / 27011, WO 98 / 050431, EP 1870459, WO 2007 / 110205, WO 2007 / 147901, WO 2009 / 089004, WO 2010 / 129304, WO 2011 / 90754, WO 2011 / 143545, WO 2012 / 058768, WO 2013 / 157954 and WO 2013 / 096291. In one embodiment, the heterodimerization method described in EP 1 870 459A1 is used instead. This method is based on the substitution / mutation of charged amino acids with opposite charges introduced at specific amino acid positions in the CH3 / CH3 domain interface between the two heavy chains. A preferred embodiment of the multispecific antibody is the amino acid R409D and K370E mutations in the CH3 domain of one heavy chain of the multispecific antibody and the amino acid D399K and E357K mutations in the CH3 domain of the other heavy chain (numbered according to the Kabat EU index). In another embodiment, the multispecific antibody comprises an amino acid T366W mutation in the CH3 domain of the "knob chain" and amino acid T366S, L368A, and Y407V mutations in the CH3 domain of the "hole chain"; and further comprises amino acid R409D and K370E mutations in the CH3 domain of the "knob chain" and amino acid D399K and E357K mutations in the CH3 domain of the "hole chain". In one embodiment, the heterodimerization method described in WO2013 / 157953 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366K mutation, and the CH3 domain of the other heavy chain comprises an amino acid L351D mutation. In another embodiment, the CH3 domain of one heavy chain further comprises an amino acid L351K mutation. In another embodiment, the CH3 domain of the other heavy chain further comprises an amino acid mutation selected from Y349E, Y349D, and L368E (in one embodiment, L368E). In one embodiment, the heterodimerization method described in WO2012 / 058768 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises amino acid mutations L351Y and Y407A, and the CH3 domain of the other heavy chain comprises amino acid mutations T366A and K409F. In another embodiment, the CH3 domain of the other heavy chain further comprises amino acid mutations at positions T411, D399, S400, F405, N390, or K392. In one embodiment, the amino acid mutation is selected from the group consisting of: a) T411N, T411R, T411Q, T411K, T411D, T411E, and T411W, b) D399R, D399W, D399Y, and D399K, c) S400E, S400D, S400R, and S400K, d) F405I, F405M, F405T, F405S, F405V, and F405W, e) N390R, N390K, and N390D, f) K392V, K392M, K392R, K392L, K392F, and K392E. In another embodiment, the CH3 domain of one heavy chain comprises amino acid mutations L351Y and Y407A, and the CH3 domain of the other heavy chain comprises amino acid mutations T366V and K409F. In another embodiment, the CH3 domain of one heavy chain comprises amino acid mutation Y407A, and the CH3 domain of the other heavy chain comprises amino acid mutations T366A and K409F. In another embodiment, the CH3 domain of the other heavy chain further comprises amino acid mutations K392E, T411E, D399R, and S400R. In one embodiment, the heterodimerization method described in WO2011 / 143545 is used instead.In one embodiment, the amino acid modification according to WO2011 / 143545 is introduced into the CH3 domain of the heavy chain at a position selected from the group consisting of 368 and 409. In one embodiment, the heterodimerization method described in WO2011 / 090762 is used instead, which also uses the above-mentioned knob-and-hole technique. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366W mutation, and the CH3 domain of the other heavy chain comprises an amino acid Y407A mutation. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid T366Y mutation, and the CH3 domain of the other heavy chain comprises an amino acid Y407T mutation. In one embodiment, the multispecific antibody is of the IgG2 isotype and the heterodimerization approach described in WO 2010 / 129304 is used instead. In one embodiment, the heterodimerization method described in WO2009 / 089004 is used instead. In one embodiment, the CH3 domain of one heavy chain comprises an amino acid substitution of K392 or N392 with a negatively charged amino acid (in one embodiment, glutamate (E) or aspartate (D); in another embodiment, a K392D or N392D mutation), and the CH3 domain of the other heavy chain comprises an amino acid substitution of D399, E356, D356 or E357 with a positively charged amino acid (in one embodiment, lysine (K) or arginine (R); in another embodiment, a D399K, E356K, D356K or E357K substitution; and in yet another embodiment, a D399K or E356K mutation). In another embodiment, the CH3 domain of one heavy chain further comprises an amino acid substitution of K409 or R409 with a negatively charged amino acid (in one embodiment, glutamate (E) or aspartic acid (D); in another embodiment, a K409D or R409D mutation). In another embodiment, the CH3 domain of one heavy chain further or alternatively comprises an amino acid substitution of K439 and / or K370 with a negatively charged amino acid (in one embodiment, glutamate (E) or aspartic acid (D)). In one embodiment, the heterodimerization method described in WO2007 / 147901 is used instead.In one embodiment, the CH3 domain of one heavy chain comprises amino acid K253E, D282K and K322D mutations, and the CH3 domain of the other heavy chain comprises amino acid D239K, E240K and K292D mutations. In one embodiment, the heterodimerization method described in WO2007 / 110205 is used instead. In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6. The invention further comprises a bispecific antibody comprising a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat); and wherein iv) in the constant heavy chain region, the T366W mutation is contained in one CH3 domain and the T366S, L368A, Y407V mutations are contained in the other CH3 domain (numbering according to the EU index of Kabat). In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF / ANG2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6. The invention further comprises a bispecific antibody comprising a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A, and P329G (numbering according to the EU index of Kabat); and wherein iv) in the constant heavy chain region, the S354C and T366W mutations are contained in one CH3 domain, and the Y349C, T366S, L368A, and Y407V mutations are contained in the other CH3 domain (numbering according to the EU index of Kabat). In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are bivalent. In one embodiment, such bispecific anti-VEGF / ANG2 antibodies are characterized in that i) the first antigen-binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain, VH, and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain, VL, and ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain, VH, and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain, VL. In one aspect of the invention, such bispecific, bivalent antibodies according to the invention are characterized in that they comprise a) the heavy and light chains of a first full-length antibody that specifically binds to VEGF; b) a modified heavy chain and a modified light chain of a second full-length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 are mutually replaced. As used herein, the term "VEGF" refers to human vascular endothelial growth factor (VEGF / VEGF-A), the 165 amino acid human vascular endothelial growth factor (amino acids 27-191 of the precursor sequence of human VEGF165: SEQ ID NO: 24; amino acids 1-26 represent the signal peptide), and the related 121, 189, and 206 vascular endothelial growth factor isoforms, as described in Leung, DW et al., Science 246 (1989) 1306-9; Houck et al., Mol. Endocrin. 5 (1991) 1806-1814; Keck, PJ et al., Science 246 (1989) 1309-12 and Connolly, DT et al., J. Biol. Chem. 264 (1989). VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors and intraocular disorders (Ferrara, N. et al., Endocr. Rev. 18 (1997) 4-25; Berkman, RA et al., J. Clin. Invest. 91 (1993) 153-159; Brown, LF et al., Human Pathol. 26 (1995) 86-91; Brown, LF et al., Cancer Res. 53 (1993) 4727-4735; Mattern, J. et al., Brit. J. Cancer. 73 (1996) 931-934; and Dvorak, HF et al., Am. J. Pathol. 146 (1995) 1029-1039). VEGF is a homodimeric glycoprotein that has been isolated from several sources and includes several isoforms. VEGF exhibits highly specific mitotic activity in endothelial cells. VEGF antagonists / inhibitors inhibit VEGF binding to its receptor, VEGFR. Known VEGF antagonists / inhibitors include bispecific anti-VEGF / ANG2 antibodies as described in WO2014 / 009465. As used herein, the term "ANG-2" refers to human angiopoietin-2 (ANG-2) (alternatively abbreviated as ANGPT2 or ANG2) (SEQ ID NO: 25), which is described, for example, in Maisonpierre, PC et al., Science 277 (1997) 55-60 and Cheung, AH et al., Genomics 48 (1998) 389-91. Angiopoietin-1 (SEQ ID NO: 26) and angiopoietin-2 are found to be ligands for Tie, a family of tyrosine kinases that are selectively expressed in the vascular endothelium (Yancopoulos, GD et al., Nature 407 (2000) 242-48). There are four identified members of the angiopoietin family. Angiopoietin-3 and angiopoietin-4 (Ang-3 and Ang-4) represent very different counterparts of the same locus in mice and humans (Kim, I. et al., FEBS Let, 443 (1999) 353-56; Kim, I. et al., J Biol Chem 274 (1999) 26523-28). ANG-1 and ANG-2 were originally identified as agonists and antagonists, respectively, in tissue culture experiments (see ANG-1: Davis, S. et al., Cell 87 (1996) 1161-69; and ANG-2: Maisonpierre, PC et al., Science 277 (1997) 55-60). All known angiopoietins bind primarily to their receptor, TIE2 (SEQ ID NO: 27), and both Ang-1 and Ang-2 bind to TIE2 with an affinity (Kd) of 3 nM (Maisonpierre, PC et al., Science 277 (1997) 55-60). ANG2 antagonists / inhibitors inhibit ANG2 binding to its receptor, TIE2. Known ANG2 antagonists / inhibitors include bispecific anti-VEGF / ANG2 antibodies as described in WO2014 / 009465. The antigen-binding site of the bispecific antibodies of the present invention contains six complementarity-determining regions (CDRs), which contribute to varying degrees to the binding site's affinity for the antigen. There are three heavy chain variable domain CDRs (CDRH1, CDRH2, and CDRH3) and three light chain variable domain CDRs (CDRL1, CDRL2, and CDRL3). The extent of the CDRs and framework regions (FRs) is determined by comparison with a compiled library of amino acid sequences, where these regions have been defined based on inter-sequence variability. The antibodies of the invention comprise immunoglobulin constant regions of human origin derived from one or more immunoglobulin classes, including IgG, IgM, IgA, IgD, and IgE classes, and in the case of IgG and IgA, subclasses thereof, particularly IgG1 and IgG4. As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of antibody molecules of a single amino acid composition. The term "chimeric antibody" refers to an antibody comprising a variable region (i.e., binding region) from one source or species and at least a portion of a constant region derived from a different source or species, which is typically prepared by recombinant DNA technology. Chimeric antibodies comprising a murine variable region and a human constant region are preferred. Other preferred forms of "chimeric antibodies" encompassed by the present invention are those chimeric antibodies in which the constant region has been modified or altered from the original antibody to produce the properties according to the present invention, particularly with respect to C1q binding and / or Fc receptor (FcR) binding. Such chimeric antibodies are also referred to as "class-switched antibodies." Chimeric antibodies are the expression products of immunoglobulin genes comprising a DNA segment encoding an immunoglobulin variable region and a DNA segment encoding an immunoglobulin constant region. Methods for producing chimeric antibodies involve conventional recombinant DNA and gene transfection techniques well known in the art. See, e.g., Morrison, SL et al., Proc. Natl. Acad. Sci. USA 81 (1984) 6851-6855; US 5,202,238 and US 5,204,244. The term "humanized antibody" refers to an immunoglobulin in which the framework or "complementarity determining regions" (CDRs) have been modified to include CDRs of an immunoglobulin with different specificity compared to the CDRs of the parent immunoglobulin. In a preferred embodiment, murine CDRs are grafted into the framework regions of a human antibody to produce a "humanized antibody." See, for example, Riechmann, L. et al., Nature 332 (1988) 323-327; and Neuberger, MS et al., Nature 314 (1985) 268-270. Particularly preferred CDRs correspond to those representing sequences recognizing the antigens mentioned above for chimeric antibodies. Other forms of "humanized antibodies" encompassed by the present invention are those in which the constant regions have been additionally modified or altered from the original antibody to produce the properties according to the present invention, particularly with respect to C1q binding and / or Fc receptor (FcR) binding. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies are well known in the art (van Dijk, MA and van de Winkel, JG, Curr. Opin. Chem. Biol. 5 (2001) 368-374). Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire or selected human antibodies in the absence of endogenous immunoglobulin production. Transfer of the human germline immunoglobulin gene array into such germline mutant mice enables the production of human antibodies upon antigen challenge (see, e.g., Jakobovits, A. et al., Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A. et al., Nature 362 (1993) 255-258; Brueggemann, M. et al., Year Immunol. 7 (1993) 33-40). Human antibodies can also be produced in phage display libraries (Hoogenboom, HR and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, JD et al., J. Mol. Biol. 222 (1991) 581-597). The techniques of Cole, A. et al. and Boerner, P. et al. can also be used to prepare human monoclonal antibodies (Cole, A. et al., Monoclonal Antibodies and Cancer Therapy, Liss, AL, p. 77 (1985); and Boerner, P. et al., J. Immunol. 147 (1991) 86-95). As already mentioned for chimeric and humanized antibodies according to the present invention, the term "human antibody" as used herein also includes such antibodies that have been modified in the constant region to produce the properties according to the present invention, particularly with respect to C1q binding and / or FcR binding, for example by "class switching", i.e., changes or mutations in the Fc portion (e.g., IgG1 to IgG4 and / or IgG1 / IgG4 mutations). As used herein, the term "recombinant antibody" is intended to include all human antibodies prepared, expressed, formed or isolated by recombinant means, such as antibodies isolated from host cells such as NS0 or CHO cells or from animals (e.g., mice) that have been transfected with human immunoglobulin genes, or antibodies expressed using recombinant expression vectors transfected into host cells. Such recombinant antibodies have variable and constant regions in rearranged form. The recombinant antibodies according to the present invention have undergone in vivo somatic hypermutation. Therefore, the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are not necessarily sequences that naturally occur within the human antibody germline repertoire in vivo. As used herein, "variable domain" (variable domain of light chain (VL), variable domain of heavy chain (VH)) refers to each of a pair of light and heavy chains that are directly involved in antibody binding to antigen. The variable domains of human light and heavy chains have the same general structure, and each domain comprises four framework (FR) regions, whose sequences are extensively conserved, connected by three "hypervariable regions" (or complementarity determining regions, CDRs). The framework regions adopt a β-sheet configuration, and the CDRs can form loops connecting the β-sheet structure. The CDRs in each chain are held in their three-dimensional structure by the framework regions and, together with the CDRs from the other chain, form the antigen binding site. The antibody heavy and light chain CDR3 regions play a particularly important role in the binding specificity / affinity of the antibodies according to the present invention and therefore provide another object of the present invention. As used herein, the terms "hypervariable region" or "antigen-binding portion of an antibody" refer to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region comprises amino acid residues from the "complementarity determining regions" or "CDRs." The "framework" or "FR" regions are those variable domain regions other than the hypervariable region residues as defined herein. Thus, the light and heavy chains of an antibody comprise, from N-terminus to C-terminus, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The CDRs on each chain are separated by these framework amino acids. In particular, CDR3 of the heavy chain is the region that contributes most to antigen binding. The CDR and FR regions are determined according to the standard definitions of Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991). The term "full-length antibody" refers to an antibody composed of two full-length heavy chains and two full-length light chains. A full-length heavy chain is a polypeptide consisting, in the N-terminal to C-terminal direction, of the antibody heavy chain variable domain (VH), the antibody constant heavy chain domain 1 (CH1), the antibody hinge region (HR), the antibody heavy chain constant domain 2 (CH2), and the antibody heavy chain constant domain 3 (CH3) (abbreviated as VH-CH1-HR-CH2-CH3), and, in the case of antibodies of the IgE subclass, the optional antibody heavy chain constant domain 4 (CH4). Preferably, a full-length heavy chain is a polypeptide consisting, in the N-terminal to C-terminal direction, of VH, CH1, HR, CH2, and CH3. A full-length light chain is a polypeptide consisting, in the N-terminal to C-terminal direction, of the antibody light chain variable domain (VL) and the antibody light chain constant domain (CL) (abbreviated as VL-CL). The antibody light chain constant domain (CL) can be kappa (κ) or lambda (λ). The two full-length antibody chains are linked together via inter-polypeptide disulfide bonds between the CL and CH1 domains and between the hinge regions of the full-length antibody heavy chains. Examples of typical full-length antibodies are natural antibodies, such as IgG (e.g., IgG1 and IgG2), IgM, IgA, IgD, and IgE. The full-length antibodies according to the present invention may be from a single species, such as humans, or they may be chimeric or humanized antibodies. The full-length antibodies according to the present invention comprise two antigen-binding sites, each formed by a VH and VL pair, which specifically bind to the same antigen. The C-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the C-terminus of the heavy or light chain. The N-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the N-terminus of the heavy or light chain. As used in this application, the term "constant region" refers to the sum of the domains of an antibody excluding the variable region. The constant region is not directly involved in binding to an antigen, but exhibits various effector functions. Depending on the amino acid sequence of the constant region of the antibody heavy chain, antibodies are divided into the following classes: IgA, IgD, IgE, IgG, and IgM, and some of these classes can be further divided into subclasses, such as IgG1, IgG2, IgG3, and IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to the different classes of antibodies are referred to as α, δ, ε, γ, and μ, respectively. The light chain constant regions that can be found in all five antibody classes are referred to as κ (kappa) and λ (lambda). As used herein, the term "constant region derived from a human source" or "human constant region" refers to a constant heavy chain region and / or a constant light chain kappa or lambda region of a human antibody of the subclass IgG1, IgG2, IgG3 or IgG4. Such constant regions are well known in the art and are described, for example, by Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, for example, Johnson, G. and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). Within application for numbering of positions and mutations, the EU numbering system (EU index) according to Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) is used and is referred to as "EU index numbering according to Kabat." In one embodiment, the bispecific antibody according to the present invention has a constant region of the human IgG1 subclass (derived from the human IgG1 subclass). However, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and the C-terminal lysine (Lys447) of the Fc region may or may not be present. In one embodiment, the bispecific antibodies described herein are of the IgG1 isotype / subclass and comprise the constant heavy chain domain of SEQ ID NO: 23 or the constant portion of the heavy chain amino acid sequence of SEQ ID NO: 17 and the constant portion of the heavy chain amino acid sequence of SEQ ID NO: 18. In one embodiment, a C-terminal glycine (Gly446) is additionally present. In one embodiment, a C-terminal glycine (Gly446) and a C-terminal lysine (Lys447) are additionally present. Unless otherwise specified herein, the numbering of amino acid residues in the constant region is according to the EU numbering system, also known as Kabat's EU index, as described in Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242. In one embodiment, the bispecific antibodies according to the present invention are of the human IgG1 subclass with the mutations L234A (Leu235Ala), L235A (Leu234Ala), and P329G (Pro329Gly). Such antibodies have reduced FcR binding (in particular, they no longer bind to FcRγI, FcRγII, and FcRγIII). This is particularly useful for reducing potential side effects, such as thrombosis (Meyer, T. et al., J. Thromb. Haemost. 7 (2009) 171-81). While the Pro329Ala mutation described above only removes two-thirds of the FcγRIIIa sandwich interaction, Pro329Gly in the antibodies according to the invention fully confer binding of the Fc portion to FcγRIII. This is particularly useful because binding to FcγIII is involved in ADCC (antibody-dependent cellular cytotoxicity), which triggers cell death, which can be helpful in treating cancerous diseases but can cause severe side effects in antibody-based therapies for other vascular or immune diseases. Thus, antibodies according to the invention of the IgG1 subclass with the mutations L234A, L235A, and P329G, and of the IgG4 subclass with the mutations S228P, L235E, and P329G, are particularly useful because they no longer bind to FcRγI, FcRγII, and FcRγIII. An "effective amount" of an agent (eg, a pharmaceutical formulation or a bispecific anti-VEGF / ANG2 antibody) refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. In one embodiment of the present invention, a bispecific antibody, drug, or pharmaceutical formulation as described herein is administered intravitreally, for example, by intravitreal injection ("intravitreal" administration). This can be performed according to standard procedures known in the art. See, for example, Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5. In some embodiments, the therapeutic kits of the present invention may contain one or more doses of the described bispecific antibodies in a drug or pharmaceutical formulation, a suitable device for intravitreal injection of the drug or pharmaceutical formulation, and instructions for performing the injection detailing the appropriate subject and regimen. In these embodiments, the drug or pharmaceutical formulation is typically administered to a subject in need of treatment via intravitreal injection. This can be performed according to standard procedures known in the art. See, for example, Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5. Regardless of the route of administration chosen, the bispecific antibodies described herein are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. One embodiment is a method of treatment or a bispecific antibody (drug or pharmaceutical formulation) for treating an ocular vascular disease as described in any of the preceding claims, wherein the antibody is administered as determined by a software tool. Another embodiment is a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from nAMD, the method comprising: receiving patient data at a computing system, the patient data comprising CST and best corrected visual acuity (BCVA); and, optionally, information regarding an assessment of new macular hemorrhage; using the computing system, extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; and obtaining the PTI based on the dosing interval for different ocular vascular diseases, such as nAMD, DME, or macular edema secondary to RVO, based on criteria as described herein. Another embodiment is a computer device / computing system for use / implementation of the method. Description of amino acid sequence In the following , List the embodiments of the present invention 1. A bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) (or a medicament or pharmaceutical formulation comprising the bispecific antibody, or a bispecific antibody for use in the preparation of a medicament), for use in treating an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), or in treating a patient suffering from an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), wherein the treatment comprises a personalized treatment interval (PTI). 2. The bispecific antibody (for use) (medicament or pharmaceutical formulation) of Example 1, for use in treating neovascular age-related macular degeneration (nAMD), or in a patient suffering from nAMD. 3. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 2, wherein the treatment comprises a personalized treatment interval, wherein a) the patient is first treated with the bispecific VEGF / ANG2 antibody four times at a 4-week (Q4W) dosing interval; b) disease activity is assessed at Week 20 and Week 24, wherein the disease activity is determined to meet one of the following criteria: i) an increase in central macular retinal thickness (CST) of >50 μm compared to the mean CST value of the two previous scheduled visits, the Week 20 assessment being for the Week 12 and Week 16 visits and the Week 24 assessment being for the Week 16 and Week 20 visits, or ii) an increase in CST of ≥75 μm compared to the lowest CST value recorded at either of the two previous scheduled visits; iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the mean BCVA value of the two previous scheduled visits due to nAMD disease activity, iv) Due to nAMD disease activity, a BCVA loss of ≥ 10 letters compared to the highest BCVA value recorded at either of the two prior scheduled visits, or v) the development of a new macular hemorrhage due to nAMD activity c) patients are then i) patients who meet disease activity criteria at Week 20 will be treated with a Q8W dosing interval beginning at Week 20 (with the first Q8W dose at Week 20); ii) patients who meet disease activity criteria at Week 24 will be treated with a Q12W dosing interval beginning at Week 24 (with the first Q12W dose at Week 24); and iii) patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval beginning at Week 28 (with the first Q16W dose at Week 28). 4. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 3, wherein after week 60, the personalized treatment interval is extended, shortened, or maintained, wherein a) if all of the following criteria are met,The interval is extended by 4 weeks (to a maximum of Q16W): i) CST is stable compared to the average of the 2 most recent study drug dosing visits, where stability is defined as a CST change of less than 30 µm and no increase of ≥ 50 µm from the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the 2 most recent study drug dosing visits and no decrease of ≥ 10 letters from the highest study drug dosing visit measurement, iii) no new macular hemorrhage; b) The interval is shortened by 4 weeks (to a minimum of Q8W) if any of the following criteria are met, or to an 8-week interval if two or more of the following criteria, or one criterion includes a new macular hemorrhage: i) CST increases by ≥ 50 µm compared to the average of the 2 most recent study drug dosing visits, or increases by ≥ 75 µm from the lowest study drug dosing visit measurement, ii) 5. A decrease in BCVA of ≥ 5 letters compared to the average of the two most recent dosing visits, or a decrease in BCVA of ≥ 10 letters compared to the highest dosing visit measurement; iii. New macular hemorrhage. 5. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 1 for treating diabetic macular edema (DME) or a patient suffering from DME. 6. The bispecific antibody (for use) (medicament or pharmaceutical formulation) of Example 5, wherein the treatment comprises a personalized treatment interval (PTI), wherein a) patients are initially treated with the bispecific VEGF / ANG2 antibody at a every 4-week (Q4W) dosing interval until central retinal thickness (CST) meets a predetermined reference CST threshold (CST <325 µm for Spectralis SD-OCT or CST <315 µm for Cirrus SD-OCT or Topcon SD-OCT) as measured at or after Week 12; b) the dosing interval is then increased by 4 weeks to an initial Q8W dosing interval; c) from this point on, the dosing interval is extended, shortened, or maintained based on assessments performed at the dosing visits, the assessments being based on the relative change in CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - The CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) maintain this interval if: - the CST decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) in the following cases,The interval is shortened by 4 weeks if - the CST value increases by >10% and ≤20%, with an associated BCVA decrease of ≥5 to <10 letters; or - the CST value increases by >20% without an associated BCVA decrease of ≥10 letters; iv) the interval is shortened by 8 weeks if the CST value increases by >10%, with an associated BCVA decrease of ≥10 letters; wherein the respective reference central macular retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive dosing visits, and such values ​​are obtained within 30 µm, so that the CST value obtained at the subsequent visit will serve as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 7. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 6, wherein the dosing interval can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. 8. A bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) for use in treating an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, or in treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI) wherein a) the patient is first treated with the bispecific VEGF / ANG2 antibody at a dosing interval of every four weeks (Q4W) from Day 1 to Week 20; and b) starting at Week 24, the patient receives the bispecific VEGF / ANG2 antibody at a frequency of Q4W until the central retinal thickness (CST) of the macula meets a predetermined reference CST threshold (CST <325 µm for Spectralis SD-OCT, or <400 µm for Cirrus CT). SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured at Week 24 or later); c) beginning at this time, extend, shorten, or maintain the dosing interval based on the relative change in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA as assessed at the dosing visits; where i) the interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if either of the following criteria is met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10%,with an associated BCVA decrease of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened to 4 weeks if any of the following criteria is met: an increase in the CST value of > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters, or an increase in the CST value of > 20% without an associated BCVA decrease of ≥ 10 letters; or an increase in the CST value of ≤ 10% with an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened to Q4W if the CST value increases by > 10% with an associated BCVA decrease of ≥ 10 letters, where the respective reference central retinal thickness (CST) is the CST value at which the initial CST threshold criteria are met and the CST decreases by > 10% of the time, the reference CST is adjusted, and the values ​​obtained are within 30 μm, such that the CST value obtained at the subsequent visit serves as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any prior dosing visit. 9. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of every 4 weeks. 10. The bispecific antibody (for use) (medicament or pharmaceutical formulation) of any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG-2 is a bispecific, bivalent anti-VEGF / ANG-2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1L region of SEQ ID NO: 1H region of SEQ ID NO: 11, and in the light chain variable domain comprises a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass,11. The bispecific antibody (for use) (medicament or pharmaceutical formulation) of Example 10, wherein i) the first antigen-binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain (VL), and ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain (VL). 12. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of Examples 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. 13. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of Examples 1 to 9, wherein the bispecific antibody is flucipirimumab. 14. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of Examples 10 to 13, wherein the bispecific antibody is administered at a dose of about 5 to 7 mg per treatment. 15. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of Examples 8 to 13, wherein the bispecific antibody is administered at a dose of about 6 mg per treatment. 16. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of embodiments 14-15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml. 17. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy. 18. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has been previously treated with an anti-VEGF therapy. 19. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of the preceding embodiments, wherein the antibody is administered according to a determination by a software tool. 20. A method of providing a personalized dosing schedule according to a personalized treatment interval (PTI) for treating a patient suffering from nAMD, the method comprising: receiving patient data at a computing system, the patient data comprising information about the patient's CST and best corrected visual acuity (BCVA) and, optionally, an assessment of new macular hemorrhage; and using the computing system,Extend, shorten, or maintain the dosing interval based on received patient data compared to the respective reference CST and BCVA; and obtain PTI based on that dosing interval, where a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the 2 most recent study drug dosing visits, where stability is defined as a change in CST of less than 30 µm and no increase in CST of ≥ 50 µm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the 2 most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement, iii) no new macular hemorrhage b) the interval is shortened by 4 weeks (to a minimum of Q8W) if any of the following criteria are met, or shortened to an 8-week interval if two or more of the following criteria, or one criterion includes new macular hemorrhage, are met: i) ii) CST increase of ≥ 50 µm compared to the average of the two most recent dosing visits, or CST increase of ≥ 75 µm compared to the lowest dosing visit measurement; ii) BCVA decrease of ≥ 5 letters compared to the average of the two most recent dosing visits, or BCVA decrease of ≥ 10 letters compared to the highest dosing visit measurement; iii) new macular hemorrhage. 21. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from diabetic renal artery disease (DME), the method comprising: receiving patient data at a computing system, the patient data comprising a CST and best-corrected visual acuity (BCVA) of the patient; and using the computing system, based on the received patient data compared to respective reference CST and BCVA, extending, shortening, or maintaining a dosing interval; and obtaining a PTI based on the dosing interval, wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) the interval is maintained if: - the CST value decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by > 10% and ≤ 20% increase in the CST value with an associated BCVA decrease of ≥ 5 to < 10 letters; or - an increase in the CST value of > 20% without an associated BCVA decrease of ≥ 10 letters; iv) in case of an increase in the CST value of > 10% with an associated BCVA decrease of ≥ 10 letters,22. A method of providing a personalized dosing schedule according to a personalized treatment interval (PTI) for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best corrected visual acuity (BCVA); and using the computing system to extend, shorten, or maintain a dosing interval based on the received patient data compared to respective reference CST and BCVA; and obtaining a PTI based on the dosing interval, wherein i) the interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria are met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 23. The method of any of embodiments 20, 21, or 22, further comprising: receiving updated patient data at the computing system; continuously updating or maintaining the dosing interval using the computing system based on the updated patient data; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval. 24. A use of a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of nAMD, wherein a computing system obtains the PTI by: receiving patient data at the computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA) and, optionally, information regarding an assessment of new macular hemorrhage; and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) the CST is stable compared to the average of the two most recent study drug dosing visits, wherein stability is defined as a CST change of less than 30 µm and no increase in CST of ≥ 50 µm compared to the lowest study drug dosing visit measurement,ii) no decrease in BCVA of ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement, iii) no new macular hemorrhage b) This interval is shortened to 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or to an 8-week interval if two or more of the following criteria are met, or one criterion includes a new macular hemorrhage: i) CST increase of ≥ 50 µm compared to the average of the two most recent dosing visits, or CST increase of ≥ 75 µm compared to the lowest dosing visit measurement; ii) BCVA decrease of ≥ 5 letters compared to the average of the two most recent dosing visits, or BCVA decrease of ≥ 10 letters compared to the highest dosing visit measurement; iii) new macular hemorrhage. 25. A use of a personalized dosing schedule based on a personalized treatment interval (PTI) for treating DME, wherein a computing system obtains the PTI by: receiving patient data comprising the patient's CST and best-corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) the interval is maintained if: - the CST decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters; or - an increase in the CST value of > 20% without an associated decrease in BCVA of ≥ 10 letters; iv) in the case of an increase in the CST value of > 10% with an associated decrease in BCVA of ≥ 10 letters, the interval is shortened by 8 weeks. 26. Use of a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein a computing system obtains the PTI by: receiving patient data comprising the patient's CST and best corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10%,or ii) maintain the interval if any of the following criteria is met: a decrease in the CST value of >10%; or a decrease in the CST value of ≤10% with an associated decrease in BCVA of ≥10 letters, or an increase in the CST value of >10% and ≤20% without an associated decrease in BCVA of ≥5 letters; iii) shorten the interval to 4 weeks if any of the following criteria is met: an increase in the CST value of >10% and ≤20% with an associated decrease in BCVA of ≥5 to <10 letters, or an increase in the CST value of >20% without an associated decrease in BCVA of ≥10 letters, or an increase in the CST value of ≤10% with an associated decrease in BCVA of ≥10 letters; iv) shorten the interval to Q4W if the CST value increases by >10% with an associated decrease in BCVA of ≥10 letters. The following are examples of the present invention: 1. A method of treating a patient suffering from an ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein the treatment comprises a personalized treatment interval (PTI). 2. The method of Example 1, wherein the ocular vascular disease is neovascular age-related macular degeneration (nAMD). 3. The method of Example 2, wherein the treatment comprises a personalized treatment interval, wherein a) patients are initially treated four times with the bispecific VEGF / ANG2 antibody at a 4-week (Q4W) dosing interval; b) disease activity is assessed at Week 20 and Week 24, wherein the disease activity is determined to meet one of the following criteria: i) an increase in central macular retinal thickness (CST) of >50 μm compared to the mean CST value of the two prior scheduled visits, with the Week 20 assessment being for the Week 12 and Week 16 visits and the Week 24 assessment being for the Week 16 and Week 20 visits, or ii) an increase in CST of ≥75 μm compared to the lowest CST value recorded at either of the two prior scheduled visits; iii) a decrease in best-corrected visual acuity (BCVA) of ≥5 letters compared to the mean BCVA value of the two prior scheduled visits due to nAMD disease activity, iv) Due to nAMD disease activity, a BCVA loss of ≥ 10 letters compared to the highest BCVA value recorded at either of the two prior scheduled visits, or v) the development of a new macular hemorrhage due to nAMD activity c) patients are then i) patients who meet disease activity criteria at Week 20 will be treated with a Q8W dosing interval beginning at Week 20 (with the first Q8W dose at Week 20); ii) patients who meet disease activity criteria at Week 24 will be treated with a Q12W dosing interval beginning at Week 24 (with the first Q12W dose at Week 24); and iii) patients who do not meet disease activity criteria at Weeks 20 and 24 will be treated with a Q16W dosing interval beginning at Week 28 (with the first Q16W dose at Week 28). 4. The method of Example 3, wherein after Week 60, the personalized treatment interval is extended, shortened, or maintained, wherein a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the two most recent study drug dosing visits, wherein stability is defined as a change in CST of less than 30 μm and no increase in CST of ≥ 50 μm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the two most recent study drug dosing visits,and no decrease in BCVA of ≥ 10 letters compared to the highest study medication visit measurement, iii) no new macular hemorrhage; b) this interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met, or one criterion includes a new macular hemorrhage: i) an increase in CST of ≥ 50 μm compared to the average of the two most recent medication visits, or an increase in CST of ≥ 75 μm compared to the lowest medication visit measurement, ii) a decrease in BCVA of ≥ 5 letters compared to the average of the two most recent medication visits, or a decrease in BCVA of ≥ 10 letters compared to the highest medication visit measurement, iii) new macular hemorrhage. 5. The method of Example 1, for treating diabetic macular edema (DME) or a patient suffering from DME. 6. The method of Example 5, wherein the treatment comprises a personalized treatment interval (PTI), wherein a) patients are initially treated with the bispecific VEGF / ANG2 antibody at a every 4-week (Q4W) dosing interval until central retinal thickness (CST) meets a predetermined reference CST threshold (CST <325 µm for Spectralis SD-OCT or CST <315 µm for Cirrus SD-OCT or Topcon SD-OCT) as measured at or after Week 12; b) the dosing interval is then increased by 4 weeks to an initial Q8W dosing interval; c) from this point on, the dosing interval is extended, shortened, or maintained based on assessments performed at the dosing visits based on the relative change in CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) maintain the interval in the following cases: - the CST decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) shorten the interval by 4 weeks in the following cases: - the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters; or - the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; iv) shorten the interval by 8 weeks in the case of an increase of > 10% with an associated BCVA decrease of ≥ 10 letters; Wherein, the respective reference central retinal thickness (CST) is the CST value when the initial CST threshold criteria are met,and adjusting the reference CST if the CST decreases by >10% relative to the previous reference CST between two consecutive dosing visits, and such values ​​are obtained within 30 μm, such that the CST value obtained at the subsequent visit serves as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 7. The method of Example 6, wherein the dosing interval can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of every Q4W. 8. A method of treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein the treatment comprises a personalized treatment interval (PTI), wherein a) the patient is initially treated with the bispecific VEGF / ANG2 antibody at a dosing interval of every four weeks (Q4W) from day 1 to week 20; and b) starting at week 24, the patient receives the bispecific VEGF / ANG2 antibody at a Q4W dosing interval until central retinal thickness (CST) meets a predetermined reference CST threshold (CST <325 µm for Spectralis SD-OCT or CST <315 µm for Cirrus SD-OCT or Topcon SD-OCT). c) beginning at that time, extend, shorten, or maintain the dosing interval based on assessments performed at those dosing visits based on the relative change in the CST and best-corrected visual acuity (BCVA) compared to the respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated decrease in BCVA of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria is met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10% with an associated decrease in BCVA of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 20% without an associated decrease in BCVA of ≥ 5 letters; iii) the interval is shortened by 4 weeks if any of the following criteria is met: an increase in the CST value of > 10% and ≤ 20% with an associated decrease in BCVA of ≥ 5 to < 10 letters, or an increase in the CST value of > 20% without an associated BCVA decrease of ≥ 10 letters; or an increase of ≤ 10% in the CST value with an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened to Q4W in the following cases: the CST value increases by > 10%,with an associated BCVA decrease of ≥ 10 letters, wherein the respective reference central macular retinal thickness (CST) is the CST value when the initial CST threshold criteria are met, and the reference CST is adjusted if the CST decreases by > 10% relative to the previous reference CST at two consecutive dosing visits, and the values ​​obtained are within 30 μm, such that the CST value obtained at the subsequent visit serves as the new reference CST; and wherein the reference best-corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 9. The method of Example 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. 10. The method of any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG-2 is a bispecific, bivalent anti-VEGF / ANG-2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) the first antigen-binding site that specifically binds to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO: 3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6; and ii) the second antigen-binding site that specifically binds to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO: 5, and a CDR1L region of SEQ ID NO: 6. 11. The method of Example 10, wherein i) the first antigen-binding site that specifically binds to VEGF comprises the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain (VL), and ii) the second antigen-binding site that specifically binds to ANG-2 comprises the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 16 as the light chain variable domain (VL). 12. The method of any one of embodiments 1 to 9,wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. 13. The method of any one of embodiments 1-9, wherein the bispecific antibody is flucipirimumab. 14. The method of any one of embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 5 to 7 mg per treatment. 15. The method of any one of embodiments 10-13, wherein the bispecific antibody is administered at a dose of about 6 mg per treatment. 16. The method of any one of embodiments 14-15, wherein the bispecific antibody is administered at a concentration of about 120 mg / ml. 17. The method of any of the preceding embodiments, wherein the patient suffering from an ocular vascular disease has not been previously treated with an anti-VEGF therapy. 18. The method of any one of the preceding embodiments, wherein the patient suffering from ocular vascular disease has previously been treated with anti-VEGF therapy. 19. The method of any one of the preceding embodiments, wherein the antibody is administered as determined by a software tool. 20. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA) and, optionally, information regarding an assessment of new macular hemorrhage; and using the computing system, extending, shortening, or maintaining a dosing interval based on the received patient data compared to respective reference CST and BCVA; and obtaining a PTI based on the dosing interval, wherein a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the two most recent study drug dosing visits, wherein stability is defined as a change in CST of less than 30 µm and no increase in CST of ≥ 50 µm compared to the lowest study drug dosing visit measurement, ii) BCVA has not decreased by ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA by ≥ 5 letters compared to the highest study drug dosing visit measurement 10 letters, iii) no new macular hemorrhage b) this interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met, or one criterion includes a new macular hemorrhage: i) CST increase of ≥ 50 µm compared to the average of the two most recent dosing visits, or CST increase of ≥ 75 µm compared to the lowest dosing visit measurement; ii) BCVA decrease of ≥ 5 letters compared to the average of the two most recent dosing visits, or compared to the highest dosing visit measurement,BCVA loss ≥ 10 letters; iii) new macular hemorrhage. 21. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from diabetic renal artery disease (DME), the method comprising: receiving patient data at a computing system, the patient data comprising a CST and best-corrected visual acuity (BCVA) of the patient; and using the computing system, based on the received patient data compared to respective reference CST and BCVA, extending, shortening, or maintaining a dosing interval; and obtaining a PTI based on the dosing interval, wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) the interval is maintained if: - the CST value decreases by > 10%, or - the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or - the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by > 10% and ≤ 20% increase in the CST value with an associated BCVA decrease of ≥ 5 to < 10 letters; or - an increase in the CST value of > 20% without an associated BCVA decrease of ≥ 10 letters; iv) in case of an increase in the CST value of > 10% with an associated BCVA decrease of ≥ 10 letters, the interval is shortened to 8 weeks. 22. A method of providing a personalized dosing schedule according to a personalized treatment interval (PTI) for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA); and using the computing system, based on the received patient data compared to respective reference CST and BCVA, extending, shortening, or maintaining a dosing interval; and obtaining a PTI based on the dosing interval, wherein i) the interval is extended for 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria are met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) this interval is shortened by 4 weeks if any of the following criteria are met: an increase in the CST value of > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters, or an increase in the CST value of > 20% without an associated BCVA decrease of ≥ 10 letters,or an increase in the CST value of ≤ 10%, with an associated decrease in BCVA of ≥ 10 letters; iv) the interval is shortened to Q4W if the CST value increases by > 10%, with an associated decrease in BCVA of ≥ 10 letters. 23. The method of any of embodiments 20, 21, or 22, further comprising: receiving updated patient data at the computing system; continuously updating or maintaining the dosing interval based on the updated patient data using the computing system; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval. 24. A use of a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of nAMD, wherein a computing system obtains the PTI by: receiving patient data at the computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA) and, optionally, information regarding an assessment of new macular hemorrhage; and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein a) the interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) the CST is stable compared to the average of the two most recent study drug dosing visits, wherein stability is defined as a CST change of less than 30 µm and no increase in CST of ≥ 50 µm compared to the lowest on-study drug dosing visit measurement, ii) there is no decrease in BCVA of ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest on-study drug dosing visit measurement, iii) No new macular hemorrhage b) This interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria, or one criterion includes a new macular hemorrhage: i) CST increase of ≥ 50 µm compared to the average of the two most recent dosing visits, or CST increase of ≥ 75 µm compared to the lowest dosing visit measurement; ii) BCVA decrease of ≥ 5 letters compared to the average of the two most recent dosing visits, or BCVA decrease of ≥ 10 letters compared to the highest dosing visit measurement; iii) new macular hemorrhage. 25. A use of a personalized dosing schedule based on a personalized treatment interval (PTI) for treating DME, wherein a computing system obtains the PTI by: receiving patient data comprising the patient's CST and best-corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein i) the interval is extended by 4 weeks if: - the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; ii) if:The interval is maintained if: - the CST decreases by >10%, or - the CST value increases or decreases by ≤10%, with an associated BCVA decrease of ≥10 letters, or - the CST value increases by >10% and ≤20%, without an associated BCVA decrease of ≥5 letters; iii) the interval is shortened by 4 weeks if - the CST value increases by >10% and ≤20%, with an associated BCVA decrease of ≥5 to <10 letters; or - the CST value increases by >20%, without an associated BCVA decrease of ≥10 letters; iv) the interval is shortened by 8 weeks in case of an increase of >10% with an associated BCVA decrease of ≥10 letters. 26. A use of a personalized dosing schedule based on a personalized treatment interval (PTI) for treating macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein a computing system obtains the PTI by: receiving patient data comprising the patient's CST and best-corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA; wherein i) the interval is extended for 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if any of the following criteria is met: a decrease in the CST value of > 10%; or a decrease in the CST value of ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or an increase in the CST value of > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; The interval is shortened to 4 weeks if any of the following criteria are met: the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters, or the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; or the CST value increases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters; iv) the interval is shortened to Q4W if the CST value increases by > 10% with an associated BCVA decrease of ≥ 10 letters. Example Treatment of Patients with Vascular Eye Disease with Bispecific Antibodies Binding to Human VEGF and Human ANG2 Example 1: Efficacy and Durability of Treatment in Patients with Neovascular Age-Related Macular Degeneration (nAMD) Using Personalized Treatment Intervals In an earlier Phase II, 52-week study investigating specifically the efficacy of RO6867461 (flucipirimumab) administered at 12 and 16 week intervals in treatment-naive patients with nAMD, some possibility of longer durability (potentially longer time to retreatment) was found in all participating patients. Three cohorts are being studied - Cohort A (Q12W): 6 mg RO6867461 intravitreal (IVT) every 4 weeks until Week 12 (4 injections), followed by 6 mg RO6867461 IVT every 12 weeks until Week 48 (injections at Weeks 24, 36, and 48; 3 injections) ................................................................................ - Cohort B (Q16W): 6 mg RO6867461 (IVT) every 4 weeks until Week 12 (4 injections), followed by 6 mg RO6867461 IVT every 16 weeks until Week 48 (injections at Weeks 28 and 44; 2 injections) ................................................................ - Cohort C (comparator cohort): 0.5 mg ranibizumab IVT every 4 weeks for 48 weeks (13 injections). Only one eye will be selected as the study eye. The results regarding BCVA are shown in Figure 5. Figure 5 shows the gain in BCVA relative to baseline in patients with neovascular age-related macular degeneration (nAMD) comparing the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab) at 12 and 16 week intervals to ranibizumab (Lucentis®) at 4 week intervals (administered intravitreally at a 0.3 mg dose). A follow-up Phase III study has begun that will now evaluate the efficacy, safety, durability, and pharmacokinetics of a 6 mg dose of flucicept administered at intervals of up to 16 weeks (via a specific personalized treatment interval (PTI) schedule) compared to aflibercept monotherapy every 8 weeks in patients with CNV secondary to AMD (also known as nAMD). Flucicept will be administered at a concentration of approximately 120 mg / ml. The specific objectives and corresponding endpoints of the study are summarized in Table 1. Table 1 Objectives and corresponding endpoints Table 1 Targets and corresponding endpoints (continued) Table 1 Targets and corresponding endpoints (continued) Patients with neovascular age-related macular degeneration (nAMD), also known as wet AMD, are treated with a bispecific antibody that binds to human VEGF and human ANG2, comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. (This antibody, VEGFang2-0016, and its production are also described in detail in WO 2014 / 009465, incorporated by reference.) This bispecific anti-VEGF / ANG2 antibody is referred to herein as RO6867461, RG7716, VEGFang2-0016, or flucipirimumab. Treatment is with an active comparator, such as aflibercept. Patients include those who are anti-VEGF therapy naive (not previously treated with anti-VEGF therapies such as aflibercept and / or ranibizumab, and / or other anti-VEGF therapies). Vials of sterile, colorless to light brown, preservative-free solution of RO6867461 (flucipirimumab) for intravitreal (IVT) administration at a 6 mg dose were used. Study Design This is a multicenter, randomized, active comparator, double-blind, parallel-group, 112-week study investigating the efficacy, safety, durability, and pharmacokinetics of flucipirimumab administered at intervals of up to 16 weeks in treatment-naive patients with nAMD. Approximately 640 patients will be enrolled globally and randomized in a 1:1 ratio to one of two treatment arms: Cohort A (flupirimumab, up to Q16W) (n=320): Patients randomized to Cohort A will receive 6 mg IVT flupirimumab Q4W through Week 12 (4 injections). At Week 20, a protocol-defined disease activity assessment requires patients in Cohort A with active disease (see below for criteria) to be treated at that visit and continue the Q8W dosing schedule of flupirimumab. A second protocol-defined disease activity assessment at Week 24 requires patients in Cohort A with active disease (excluding those with active disease at Week 20 who therefore received the Q8W dosing schedule of flupirimumab) to be treated at that visit and continue the Q12W dosing schedule of flupirimumab. Patients receiving flucirex who do not have active disease according to protocol-defined criteria at Weeks 20 and 24 will be treated with flucirex every 16 weeks. Based on disease activity assessments at Weeks 20 and 24, patients will continue to receive flucirex every 8, 12, or 16 weeks on a fixed schedule until Week 60. Beginning at Week 60 (when all patients in Cohort A are scheduled to receive flucirex), all patients in Cohort A will be treated according to a personalized treatment interval (PTI) dosing schedule (see Table 2 for PTI dosing criteria) until Week 108. Cohort B (Comparator Cohort) (Q8W): Patients randomized to Cohort B will receive 2 mg IVT aflibercept every 4 weeks until Week 8 (3 injections), followed by 2 mg IVT aflibercept every 8 weeks until Week 108. Patients in both treatment arms will complete Q4W scheduled study visits throughout the study duration (112 weeks). Patients in both treatment arms will be administered sham procedures at study visits without study treatment administration to maintain masking between treatment arms. Figure 1 presents an overview of the study design. a) Patients will undergo disease activity assessments at Weeks 20 and 24. Patients with anatomical or functional signs of disease activity at these time points will receive dosing every 8 weeks or every 12 weeks, respectively, rather than every 16 weeks. b) The primary endpoint is the change from baseline in BCVA (as assessed on the ETDRS chart at a 4-meter starting distance) based on the mean values ​​at Weeks 40, 44, and 48. c) Beginning at Week 60 (when all patients in Cohort A are scheduled to receive fluvicytumomab), patients in Cohort A will be treated according to the PTI dosing schedule (between every 8 weeks and every 16 weeks). BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; IVT = intravitreal; PTI = personalized treatment interval; Q8W = every 8 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; W = week. Only one eye will be designated as the study eye. If both eyes are deemed eligible (according to the inclusion and exclusion criteria) at the screening assessment, the eye with the worse BCVA will be selected as the study eye (unless, for medical reasons, the investigator deems the other eye more suitable for treatment in the study). At least two investigators will be present at each site to meet the study's masking requirements. At least one investigator will be designated as the assessing physician, who will be masked to each patient's treatment assignment and will evaluate ocular assessments. At least one other investigator will be unmasked and will administer the study treatment. The study will consist of a screening period of up to 28 days (-28 days to -1 day) and a treatment period of approximately 108 weeks, followed by a final study visit at Week 112 (at least 28 days after the last dose of study treatment). No. 20 week Pass the exam twenty four week Disease Activity Criteria Active disease will be determined at Weeks 20 and 24 as meeting any of the following criteria: ● CST increase > 50 μm compared to the average CST value of the two previous scheduled visits (Week 20 assessment is for Week 12 and Week 16 visits, and Week 24 assessment is for Week 16 and Week 20 visits); or ● CST increase ≥ 75 μm compared to the lowest CST value recorded at either of the two previous scheduled visits; or ● BCVA decrease of ≥ 5 letters (as determined by the investigator) compared to the average BCVA value of the two previous scheduled visits due to nAMD disease activity; or ● BCVA decrease of ≥ 10 letters (as determined by the investigator) compared to the highest BCVA value recorded at either of the two previous scheduled visits due to nAMD disease activity; or ● Appearance of new macular hemorrhage due to nAMD activity (as determined by the investigator). No. twenty four week Additional considerations when Patients randomized to Cohort A who have significant nAMD disease activity at Week 24 that does not meet the above criteria, but who, in the investigator's opinion, would otherwise warrant treatment, will receive 6 mg of fluvicipizumab at Week 24 and continue to receive repeated 12-week treatment. Patients randomized to Cohort A who meet disease activity criteria at Week 20 will remain on their Q8W dosing schedule and will not receive treatment at Week 24. Patients randomized to Cohort B will remain on their Q8W dosing schedule and will receive aflibercept at Week 24. Personalized treatment intervals (PTI) Disease activity criteria begin at Week 60, when all patients in Cohort A are scheduled to receive fluvicepimab. The study drug dosing interval for patients in Cohort A will be extended based on assessments performed at the study drug dosing visit. The study drug dosing interval decisions (and respective algorithms) for Cohort A during the PTI protocol phase are described in Table 2. Decisions will be made based on data from the patient's on-drug visit. When patients are not receiving treatment with fluvicepimab, they will receive a sham procedure at the study visit. Table 2 Personalized treatment interval algorithm As summarized above in Table 2, the algorithm used to make personalized medication interval decisions is based on the relative change in CST and the absolute change in BCVA compared to the reference CST and BCVA, respectively; and additionally on the assessment / finding of new macular hemorrhages. The algorithm can be implemented by a computing system or device. This computing system or device can include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing scheduling or notifications, monitor and generate visualizations of dosing interval changes for a given patient, generate visualizations of dosing interval changes for a group of patients, summarize the received CST and BCVA data to determine trends, or a combination thereof. Dosing schedules or notifications may include calendar reminders that display the calendar date for scheduled dosing visits and notify the clinician or patient of upcoming dosing visits. Visualizations of dosing interval changes may include, for example, a schematic display such as in Table 2. In one instance, a patient's dosing interval adjustment may be displayed in one color, and the patient's immediately previous dosing interval adjustment may be displayed in another color. For example, a patient may first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool may generate a visualization of a patient's personalized interval progression by displaying the "Interval Maintenance" area of ​​the schematic in Table 2 in green and "Interval Extended by 4 Weeks" in yellow. Green may reflect the patient's most recent interval calculation and yellow may depict the results of the patient's immediately previous interval calculation. With this visualization, the user of the tool can quickly determine that a patient's disease progression is improving, but not to the extent that their treatment interval can be extended further. The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Similar to the color coding example described previously, such data analysis can include visualizations of dosing changes for a single patient. Alternatively, visualizations can display dosing adjustments for a patient group. For example, a visualization can display which patients have interval extensions and which patients have interval shortenings. This visualization can be organized by various features, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, etc. The tool can also aggregate patient CST and BCVA data and generate visualizations based on the data. Visualizations can display trends in data to facilitate or generate longitudinal analysis. These visualizations can include reminders, curves, analysis workflow interfaces, or any graphical interfaces. The tool can generate a dosing schedule output or visualization in response to or in conjunction with the ocular assessment and images. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture ocular images. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST based on ocular images. Regarding BCVA, the tool can virtually manage ocular assessments, prompting and collecting patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track disease progression for each patient and adjust the dosing schedule accordingly. Embodiments of the present invention may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient with nAMD, the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA); using the computing system, based on the received patient data compared to respective reference CST and BCVA, extending, shortening, or maintaining the dosing interval; and obtaining a PTI based on the dosing interval. An exemplary dosing interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST is stable compared to the average of the two most recent study drug dosing visits, where stability is defined as a CST change of less than 30 μm and no increase in CST of ≥ 50 μm compared to the lowest study drug dosing visit measurement; ii) no decrease in BCVA of ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement; and iii) no new macular hemorrhage. An exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met, or one criterion includes a new macular hemorrhage: i) a CST increase of ≥ 50 μm compared to the average of the two most recent dosing visits, or a CST increase of ≥ 75 μm compared to the lowest dosing visit measurement, ii) a decrease in BCVA of ≥ 5 letters compared to the average of the two most recent dosing visits, or a decrease in BCVA of ≥ 10 letters compared to the highest dosing visit measurement, iii) a new macular hemorrhage. This method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from nAMD may further include receiving updated patient data at a computing system; continuously updating or maintaining the dosing interval based on the updated patient data using the computing system; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval. Embodiments of the present invention also include the use of a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of nAMD, wherein a computing system obtains the PTI by: receiving patient data comprising the patient's CST and best-corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA. An exemplary dosing interval is extended by 4 weeks (to a maximum of Q16W) if all of the following criteria are met: i) CST stability compared to the average of the two most recent study drug dosing visits, where stability is defined as a CST change of less than 30 μm and no increase in CST of ≥ 50 μm compared to the lowest study drug dosing visit measurement; ii) no decrease in BCVA of ≥ 5 letters compared to the average of the two most recent study drug dosing visits and no decrease in BCVA of ≥ 10 letters compared to the highest study drug dosing visit measurement; and iii) no new macular hemorrhage. An exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or shortened to an 8-week interval if two or more of the following criteria are met, or one criterion includes a new macular hemorrhage: i) a CST increase of ≥ 50 μm compared to the average of the two most recent dosing visits, or a CST increase of ≥ 75 μm compared to the lowest dosing visit measurement; ii) a BCVA decrease of ≥ 5 letters compared to the average of the two most recent dosing visits, or a BCVA decrease of ≥ 10 letters compared to the highest dosing visit measurement; iii) a new macular hemorrhage. Eye Review The eye assessment will include the following and will be performed at designated time points: ● Using three Precision Vision TMBCVA will be measured using the Lighthouse distance visual acuity chart (modified ETDRS charts 1, 2, and R). A VA handbook will be provided to the investigator. Before performing any VA examination, obtain certification for the VA examiner and the VA examination room. The BCVA examiner will be masked to the study eye and treatment assignment and will only perform refraction and BCVA assessments (e.g., vision specification handbook). The BCVA examiner will also be masked to the patient's BCVA letter score from the previous visit and will only know the patient's refraction data from the previous visit. The BCVA examiner will not be allowed to perform any other tasks involving direct patient care. ● Low-light BCVA, as assessed on the ETDRS chart at the starting distance of the 4-meter low-light best-corrected visual acuity test. The same requirements apply as for best-corrected visual acuity described in Appendix 4; however, low-light best-corrected visual acuity will be measured by placing a 2.0 log neutral density filter (Kodak Wratten 2.0 neutral density filter) over the eye's best correction and having the participant read a normally illuminated Early Treatment Diabetic Retinopathy Study chart. ● Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before dilating the eye). ● Slit lamp examination (for grading of anterior muscle and vitreous cells, see Foster CS, Kothari S, Anesi SD, et al., The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016) 1-17). ● Dilated binocular indirect high-power ophthalmoscopy. ● Dilated eye count test, followed by hand movements and light perception test (if needed) performed only by the unmasked treatment administrator within 15 minutes after the study treatment of the study eye. ● Post-treatment IOP measurement of the study eye only within 30 (±15) minutes at the study treatment visit by qualified personnel assigned an unmasked role. If there are no safety concerns 30 (±15) minutes after the study treatment, the patient will be allowed to leave the clinic. If the IOP value is of concern to the treatment administrator, the patient will remain in the clinic and will be managed according to the clinical judgment of the treatment administrator. When appropriate, adverse events will be recorded on the electronic case report form (eCRF). The method used for IOP measurement in patients must remain constant throughout the study. The Ocular Imaging Central Reading Center (CRC) will provide sites with a Central Reading Center manual and training materials for designated study ocular images. Prior to obtaining any study images, site personnel, test images, systems, and software (where applicable) will be certified and validated by the reading center as specified in the Central Reading Center manual. All ocular image results will be obtained by trained site personnel at the study site and forwarded to the Central Reading Center for independent analysis and / or storage. After randomization, if a patient missed a study visit when ocular imaging was scheduled or if an image was not obtained at the scheduled visit (e.g., because of broken equipment), the image should be obtained at the next scheduled visit that the patient attended. Ocular imaging will include the following: ● Color fundus photography (CFP) of both eyes. Stereoscopic color fundus photographs will be obtained from both eyes by trained personnel at the study site. Fundus photography will be performed at intervals specified in the activity schedule. ● Fundus fluorescein angiography (FFA) of both eyes (performed after laboratory specimens are obtained). Fundus fluorescein angiography will be performed on both eyes at the study site by trained personnel certified by the central reading center. Fundus fluorescein angiography will be obtained at intervals specified in the protocol. ● Spectral domain optical coherence tomography (SD-OCT) or swept source OCT (SS-OCT) images of both eyes. ● Optional OCT-angiography (OCT-A) of both eyes at sites with agreed-upon OCT-A capabilities. ● Optional ICGA of both eyes at selected sites with agreed-upon ICGA capabilities (performed after laboratory specimens are obtained). Circulatory green angiography (ICGA) will be performed on both eyes at designated intervals by trained personnel certified at a central reading center. Results The primary efficacy analysis included all randomized patients, with patients assigned according to randomized treatment. The primary efficacy variable is the change in BCVA.The primary efficacy analysis will be performed using, for example, a mixed model with repeated measurements model (MMRM). Best corrected visual acuity (BCVA) was measured as described. The primary efficacy outcome measure is shown in a graph showing the primary efficacy endpoint: change in patient BCVA over time relative to baseline. According to the study protocol described above, the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, was administered intravitreally at 6.0 mg using a personalized treatment interval as described in Cohort A, compared to, for example, Cohort B (aflibercept (Eylea®) administered every 8 weeks). Central macular retinal thickness relative to baseline (CST) of change ( Studying the Eyes The key secondary endpoint was the change in CST (central macular retinal thickness) from baseline. CST (and retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in a figure showing the change in CST over time for the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, administered intravitreally at 6.0 mg as described in Cohort A using a personalized treatment interval, compared to Cohort B (aflibercept (Eylea®) administered every 8 weeks) according to the study protocol described above. Other results of eye assessment and imaging can therefore be displayed. Example 2: Efficacy and Durability of Bispecific Anti-VEGF / ANG2 Therapy in Patients with Diabetic Macular Edema (DME) Using Personalized Treatment Intervals In an early Phase II, 36-week study in patients with diabetic macular edema (DME), some potential for longer durability (possibly longer time to retreatment) was identified in all participating patients. The three study groups were treated as follows: Cohort A: 0.3 mg ranibizumab intravitreal (IVT); Cohort B: 1.5 mg RO6867461 (flucipirimumab) IVT; Cohort C: 6 mg RO6867461 (flucipirimumab) IVT. Results regarding the potential longer time to retreatment for RO6867461 (flucipirimumab, VA2) are shown in Figure 6. Figure 6 shows the time to retreatment in DME patients (after 20 weeks or 6-monthly dosing = time since the last intravitreal (IVT) dose) after dosing had stopped based on disease activity assessed by: BCVA loss ≥ 5 letters and CST increase ≥ 50 μm (= patients with an event). The bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab) (administered intravitreally at a dose of 6.0 mg or 1.5 mg) was compared to ranibizumab (Lucentis®) (administered intravitreally at a dose of 0.3 mg). A follow-up Phase III study has begun, which will now evaluate the efficacy, safety, and pharmacokinetics of RO6867461 (flucipirimumab) when administered every 8 weeks (Q8W) on a personalized treatment interval (PTI) schedule, compared to aflibercept (Eylea®) monotherapy in patients with DME. The effect on visual function will be assessed by measuring the change from baseline in best-corrected visual acuity (BCVA) (i.e., the number of ETDRS letters). The effect on retinal anatomy will be assessed using retinal imaging (spectral domain optical coherence tomography [SD-OCT], color fundus photography [CFP], fundus fluorescein angiography [FFA]) and other imaging modalities that assess both DME and DR outcomes. Additionally, the safety, patient-reported outcomes (PROs), and pharmacokinetics of RO6867461 will be evaluated. This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 when administered Q8W in a PTI regimen compared to aflibercept (Eylea®) monotherapy in patients with DME. The specific objectives and corresponding endpoints of the study are summarized in Table 3. Table 3 Objectives and corresponding endpoints Table 3 Targets and corresponding endpoints (continued) Table 3 Targets and corresponding endpoints (continued) Table 3 Targets and corresponding endpoints (continued) Patients with DME (e.g., central diabetic macular edema (CI-DME)) are treated with a bispecific antibody that binds to human VEGF and human ANG2, comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 (this antibody, VEGFang2-0016, and its production are also described in detail in WO 2014 / 009465, incorporated by reference). This bispecific anti-VEGF / ANG2 antibody is referred to herein as RO6867461, RG7716, VEGFang2-0016, or flucipirimumab. Aflibercept, for example, is used as an active comparator in the treatment. Patients include those who are naive to anti-VEGF therapy (not previously treated with anti-VEGF therapies such as aflibercept and / or ranibizumab and / or other anti-VEGF therapies) as well as a group of patients who have previously been treated with anti-VEGF therapy. Use a sterile, colorless to light brown, preservative-free vial of RO6867461 (Flucipine) solution for 6 mg doses of intravitreal (IVT) administration. RO6867461 (Flucipine) will be administered at a concentration of approximately 120 mg / ml. During the global registration phase of the study, approximately 900 patients will be randomized in a 1:1:1 ratio to one of three treatment arms at approximately 240 investigational sites worldwide (see Figure 2). The study will randomize patients with DME whose study eye is naive to anti-VEGF therapy and whose study eye has been previously treated with anti-VEGF therapy, provided that the last treatment was at least 3 months prior to the Day 1 visit (first study treatment). Site investigators will be retina specialists. The study treatment arms will be as follows (see also Figure 2): Cohort A (Q8W dosing): Patients randomized to Cohort A will receive Q4W 6-mg IVT RO6867461 (flucipirimumab) injections through Week 20, followed by Q8W 6-mg IVT RO6867461 (flucipirimumab) injections through Week 96, followed by the final study visit at Week 100. Cohort B (Personalized Treatment Interval (PTI)): Patients randomized to Cohort B will receive Q4W 6-mg IVT RO6867461 (flucipirimumab) injections through at least Week 12, followed by PTI dosing (see PTI dosing guidelines below) of 6-mg IVT RO6867461 (flucipirimumab) injections through Week 96, followed by the final study visit at Week 100. Cohort C (Comparator Cohort) (Q8W dosing): Patients randomized to Cohort C will receive 2-mg IVT aflibercept Q4W until Week 16, followed by 2-mg IVT aflibercept Q8W until Week 96, followed by a final study visit at Week 100. Patients in all three treatment arms will complete the Q4W scheduled study visits throughout the study duration (100 weeks). Patients in all three treatment arms will be administered sham procedures at applicable visits to maintain masking between treatment arms (see picture 2-Study treatment options). Only one eye will be designated as the study eye. If both eyes are deemed eligible at the screening assessment, the eye with the worse BCVA will be selected as the study eye unless the investigator deems the other eye more suitable for the treatment in the study. At least two research staff will be present at each site to meet the study's masking requirements. At least one research staff will be designated as the assessing physician, who will be masked to each patient's treatment assignment and will assess the ocular assessments. At least one other research staff member will be unmasked and will administer the study treatment (see Section 4.2.2 for additional masking details). For personalized treatment intervals (PTI) Team ( Team B) Zhongzhi The dosing interval decisions for patients in the PTI cohort are described in this section. The study drug dosing visit is the visit at which the patient is assigned to receive fluvicipizumab (RO6867461). Patients randomized to the PTI cohort (Cohort B) will receive fluvicipizumab at a quarterly dosing interval until their CST meets the predefined reference CST cutoff (CST <325 µm for Spectralis SD-OCT or <315 µm for Cirrus SD-OCT or Topcon SD-OCT) at Week 12 or later. The reference CST will be used for interval decisions at the study drug dosing visit. After the patient's initial reference CST is determined, their study drug dosing interval will be increased by 4 weeks to an initial Q8W dosing interval. From this point on, the study drug dosing interval will be extended, shortened, or maintained based on assessments performed at the study drug dosing visit. Figure 3 summarizes the algorithm used for interval decisions based on the relative changes in CST and BCVA compared to a reference CST and a reference BCVA. In Figure 3, * and ** mean the following: *Reference central retinal thickness (CST): The CST value at which the initial CST threshold criteria are met. The reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST between two consecutive study drug dosing visits, and the values ​​obtained are within 30 μm. The CST value obtained at the subsequent visit will serve as the new reference CST, starting immediately at that visit. **Reference best-corrected visual acuity (BCVA): The average of the three best BCVA scores obtained at any previous dosing visit. All comparisons were made with respect to reference CST* and reference BCVA**. Medication dosing intervals were determined based on CST and BCVA data obtained from the medication dosing visit. In the following cases, Interval extension 4 Weekly: ● CST value increases or decreases ≤ 10%, Without associated BCVA loss ≥ 10 letters In the following cases, interval maintain :● CST reduction> 10%, or ● CST value increases or decreases ≤ 10%, With associated BCVA loss ≥ 10 letters, or ● CST value increases by > 10% and ≤ 20%, without an associated BCVA loss of ≥ 5 letters; In the following cases, Shortened interval 4 Weekly: ● CST value increases by > 10% and ≤ 20%, With associated BCVA loss ≥ 5 to < 10 letters, or ● CST value increases by > 20%, Without associated BCVA loss ≥ 10 letters In the following cases, Shortened interval 8 Week: ● CST value increase > 10% with associated BCVA loss ≥ 10 letters *Reference central retinal thickness (CST): The CST value at which the initial CST threshold criteria are met. The reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST between two consecutive study drug dosing visits, and the values ​​obtained are within 30 μm. The CST value obtained at the subsequent visit will serve as the new reference CST, starting immediately at that visit. **Reference best-corrected visual acuity (BCVA): The average of the three best BCVA scores obtained at any previous dosing visit. The personalized medication dosing interval can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. The algorithm used to make personalized medication treatment interval decisions is based on the relative change in CST and the absolute change in BCVA compared to the reference CST and BCVA, respectively. The algorithm can be implemented by a computing system or device. This computing system or device can include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing scheduling or notifications, monitor and generate visualizations of dosing interval changes for a given patient, generate visualizations of dosing interval changes for a group of patients, summarize the received CST and BCVA data to determine trends, or a combination thereof. Dosing schedules or notifications may include calendar reminders that display the calendar date for a scheduled dosing visit and notify the clinician or patient of an upcoming dosing visit. Visualizations of dosing interval changes may include, for example, the schematic display in FIG3 . In one instance, a patient's dosing interval adjustment may be displayed in one color, and the patient's immediately previous dosing interval adjustment may be displayed in another color. For example, a patient may first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool may generate a visualization of a patient's personalized interval progression by displaying the "Interval Maintenance" area of ​​the schematic in green and "Interval Extended 4 Weeks" in yellow in FIG3 . Green may reflect the patient's most recent interval calculation and yellow may depict the results of the patient's immediately previous interval calculation. With this visualization, the user of the tool can quickly determine that a patient's disease progression is improving, but not to the extent that their treatment interval can be extended further. The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Similar to the color coding example described previously, such data analysis can include visualizations of dosing changes for a single patient. Alternatively, visualizations can display dosing adjustments for a patient group. For example, a visualization can display which patients have interval extensions and which patients have interval shortenings. This visualization can be organized by various features, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, etc. The tool can also aggregate patient CST and BCVA data and generate visualizations based on the data. Visualizations can display trends in data to facilitate or generate longitudinal analysis. These visualizations can include reminders, curves, analysis workflow interfaces, or any graphical interfaces. The tool can generate a dosing schedule output or visualization in response to or in conjunction with the ocular assessment and images. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture ocular images. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST based on ocular images. Regarding BCVA, the tool can virtually manage ocular assessments, prompting and collecting patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track disease progression for each patient and adjust the dosing schedule accordingly. Embodiments of the present invention may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from diabetic renal artery disease (DME), the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA); using the computing system to extend, shorten, or maintain a dosing interval based on the received patient data compared to respective reference CST and BCVA; and obtaining a PTI based on the dosing interval. An exemplary dosing interval is extended by 4 weeks if a CST value increase or decrease is ≤ 10% without an associated BCVA decrease of ≥ 10 letters. An exemplary dosing interval is maintained if: a CST decrease is > 10%, a CST value increase or decrease is ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or a CST value increase is > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters. The exemplary dosing interval is shortened to 4 weeks in the following cases: CST value increases by >10% and ≤20%, with an associated BCVA decrease of ≥5 to <10 letters; or CST value increases by >20% without an associated BCVA decrease of ≥10 letters. In the case of a CST value increase of >10% with an associated BCVA decrease of ≥10 letters, the exemplary dosing interval is shortened to 8 weeks. This method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from DME may further include receiving updated patient data at a computing system; continuously updating or maintaining the dosing interval based on the updated patient data using the computing system; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval. Embodiments of the present invention also include the use of a personalized dosing schedule based on a personalized treatment interval (PTI) for treating DME, wherein a computing system obtains the PTI by: receiving patient data including the patient's CST and best-corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared to respective reference CST and BCVA. An exemplary dosing interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters. An exemplary dosing interval is maintained if: the CST decreases by > 10%, or the CST value increases or decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters. The exemplary dosing interval is shortened to 4 weeks in the following cases: - CST value increases by > 10% and ≤ 20%, with an associated BCVA decrease of ≥ 5 to < 10 letters; or CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters. In the case of a CST value increase of > 10% with an associated BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened to 8 weeks. Similar to Cohorts A and C, patients randomized to the PTI cohort (Cohort B) will receive a sham procedure at the study visit when the patient has not received treatment with fluvicipizumab. Eye Review The scheduled eye assessment includes the following and will be performed on both eyes at designated time points according to the activity schedule: • Refraction and BCVA assessed on the ETDRS chart at a starting distance of 4 meters. TMBCVA will be measured using the Lighthouse distance visual acuity chart (modified ETDRS charts 1, 2, and R). A VA handbook will be provided to the investigator. Before performing any VA examination, the VA examiner and the VA examination room will be certified. The BCVA examiner will be masked to the study eye and treatment assignment and will only perform refraction and BCVA assessments (e.g., visual acuity specifications handbook). The BCVA examiner will also be masked to the patient's BCVA letter score from the previous visit and will only know the patient's refraction data from the previous visit. The BCVA examiner will not be allowed to perform any other tasks involving direct patient care. • Pre-treatment IOP (intraocular pressure) measurement of both eyes (performed before dilating the eyes). • Slit lamp examination (for grading of anterior muscle and vitreous cells, see Foster CS, Kothari S, Anesi SD, et al., The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016)1-17). • Dilated binocular indirect high-power ophthalmoscopy. • A digital counting test, followed by a manual motion and light perception test (when needed) performed only by the unmasked treatment administrator within approximately 15 minutes after study treatment in the study eye. • Post-treatment IOP measurement of the study eye only at 30 (±15) minutes at the study treatment visit by qualified personnel assigned an unmasked role. If there are no safety concerns after 30 (±15) minutes after study treatment, the patient will be allowed to leave the clinic. If the IOP value is of concern to the treating administrator, the patient will remain in the clinic and will be managed according to the clinical judgment of this physician. Adverse events will be recorded on the Adverse Event Electronic Case Report Form (eCRF) when appropriate. The method used for IOP measurement of the patient must remain constant throughout the study. The Ocular Imaging Central Reading Center (CRC) will provide sites with a CRC manual and training materials specific to study ocular images. Prior to obtaining any study images, site personnel, test images, systems, and software (where applicable) will be certified and validated by the CRC as specified in the CRC manual. All ocular image results will be obtained by trained site personnel at the study site and forwarded to the CRC for independent analysis and / or storage. After randomization, if a patient misses a study visit when ocular CFP and FFA imaging is scheduled or if images are not obtained at the scheduled visit (e.g., because of broken equipment), images should be obtained at the next scheduled visit in which the patient attends. Eye imaging includes the following: ● Required color fundus photography (CFP) of both eyes (7 or 4 widefield; one of these methods will be performed for patients who remain in the entire trial). Stereoscopic color fundus photographs will be obtained from both eyes by trained personnel at the study site. Fundus photography will be performed at intervals specified in the activity schedule. ● Optional ultra-widefield (UWF; Optoscopy) of both eyes ® ) CFP (at sites with UWF CFP capability and consent to obtain these images in addition to the mandatory CFP images) ● Fundus fluorescein angiography (FFA) of both eyes will be performed at the study site by trained personnel (throughout trial participation, where the site has capability, the preferred method is UWF (Optos) FFA; sites without UWF (Optos) FFA use the same method to capture 7 or 4 wide-fields (after obtaining a blood sample, if feasible). UWF (Optos) is the preferred method for Fundus fluorescein angiography (FFA) capture. Study sites without Optos equipment and certification must use 7 or 4 wide-field FFA captures. ● Spectral Domain Optical Coherence Tomography (SD-OCT) or Swept Source OCT (SS-OCT) images of both eyes. ● Optional OCT-Angiography (OCT-A) of both eyes at sites with OCT-A capability and consent by the site to obtain these images. Results The primary efficacy analysis included all randomized patients, with patients assigned according to randomized treatment. The primary efficacy variable is the change in BCVA as described herein.The primary efficacy analysis will be performed using, for example, a mixed model with repeated measurements model (MMRM). Best corrected visual acuity (BCVA) was measured as described. The primary efficacy outcome measure is shown in a graph showing the primary efficacy endpoint: change in patient BCVA over time relative to baseline. According to the study protocol described above, the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, was administered intravitreally at 6.0 mg using a personalized treatment interval as described in Cohort B, compared to, for example, Cohort A (flucipirimumab administered every 8 weeks) and / or Cohort C (aflibercept (Eylea®) administered every 8 weeks). Central macular retinal thickness relative to baseline (CST) of change ( Studying the Eyes The key secondary endpoint was the change in CST (central macular retinal thickness) from baseline. CST (and retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in a figure showing the change in CST over time for the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, administered intravitreally at 6.0 mg using a personalized treatment interval as described in Cohort B. This antibody was compared to Cohort A (flucipirimumab administered every 8 weeks) and / or Cohort C (aflibercept (Eylea®) administered every 8 weeks), according to the study protocol described above. Other results of eye assessment and imaging can therefore be displayed. Example 3: Efficacy and Durability of Bispecific Anti-VEGF / ANG2 Therapy in Patients with Macular Edema Secondary to Retinal Vein Occlusion (RVO) (Macular Edema Secondary to Central Retinal Vein Occlusion (CRVO), Hemiretinal Vein Occlusion (HRVO), or Branch Vein Occlusion (BRVO)) Using Personalized Treatment Intervals Nonclinical studies have demonstrated that Ang-2 and VEGF act synergistically to modulate vascular structure and increase retinal endothelial cell permeability in vitro. Simultaneous inhibition of Ang-2 and VEGF with the bispecific monoclonal antibody flucipirimumab resulted in greater reductions in leakage and severity of choroidal neovascularization (CNV) lesions in a laser-induced CNV model in non-human primates compared to molar equivalents of anti-VEGF (ranibizumab) or anti-Ang-2 alone. Early experiments using a mouse model of spontaneous CNV showed that dual inhibition of Ang-2 and VEGF consistently outperformed monotherapy inhibition of either target alone in terms of reductions in vessel growth, leakage, edema, leukocyte infiltration, and loss of light-receiving organs (Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288). In addition, aqueous humor and vitreous concentrations of both Ang-2 and VEGF were shown to be upregulated in patients with neovascular age-related macular degeneration (nAMD), DR, and RVO (Tong JP, Chan WM, Liu DT, et al., Am J Ophthalmol 2006;141:456-462; Penn JS, Madan A, Caldwell RB, et al., Prog Retin Eye Res 2008;27:331-371.; Kinnunen K, Puustjärvi T, Teräsvirta M, et al., Br J Ophthalmol 2009;93:1109-1115; Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099; Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288; Ng DS, Yip YW, Bakthavatsalam M, et al., Sci Rep 2017;7:45081). Therefore, simultaneous neutralization of both Ang-2 and VEGF, compared with anti-VEGF therapy alone, may further normalize pathological ocular vasculature. Data from full-scale Phase II studies in DME and nAMD (see below) also support the hypothesis that targeting Ang-2 has the potential to prolong the durability of efficacy beyond anti-VEGF therapy alone in diseases affecting retinal vasculature. Fluximab has been studied for the treatment of nAMD and DME in two Phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME). Four global Phase III studies are ongoing: GR40349 (YOSEMITE) and GR40398 (RHINE) for DME, and GR40306 (TENAYA) and GR40844 (LUCERNE) for nAMD. Based on the mechanism of action of fluvicipizumab, data from nonclinical and clinical trials, and the pathophysiology of macular edema due to RVO, it was hypothesized that fluvicipizumab may cause stabilization of pathological ocular vascular structures and improve the visual and anatomical outcomes of RVO compared to anti-VEGF monotherapy. Macular edema secondary to / due to RVO is the most common retinal vascular disease (Aiello LP, Avery RL, Arrigg PG, et al., N Engl J Med 1994;331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288). The efficacy of Ang-2 and VEGF inhibition in nonclinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016;8:1265-1288) and data from phase I and II studies of fluvicipizumab in patients with nAMD and DME provide evidence of efficacy against pathological pathways common to all three retinal vascular diseases, nAMD, DME / DR, and macular edema due to RVO (Phase I study: BP28936 in nAMD; Phase II studies: AVENUE in nAMD, STAIRWAY in nAMD, and BOULEVARD in DME). Due to the similarities in pathophysiology between DME and macular edema due to RVO, data from the Phase II BOULEVARD study are reported here. Although the triggers of macular edema in diabetic and RVO patients are different, the downstream pathophysiology of hypoxia-driven macular edema and subsequent visual loss is similar and driven by the same pro-angiogenic, pro-inflammatory, vascular instability, and vascular permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6). Results regarding the potential longer time to retreatment with RO6867461 (flucipirimumab, VA2) are shown in Figure 6. Figure 6 shows the time to retreatment in DME patients after drug discontinuation (after 20 weeks or 6-monthly dosing = time since the last intravitreal (IVT) administration) based on disease activity assessed by: BCVA loss ≥ 5 letters and CST gain ≥ 50 μm (= patients with an event). The bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), administered intravitreally at doses of 6.0 mg or 1.5 mg, was compared to ranibizumab (Lucentis®), administered intravitreally at a dose of 0.3 mg. The BOULEVARD study provides foundational evidence for a positive benefit / risk profile of 6-mg IVF flucizumab injection in patients with DME and supports further evaluation of flucizumab in a Phase III DME study. The study met its primary efficacy endpoint, demonstrating a statistically significant improvement in mean change from baseline BCVA at Week 24 in anti-VEGF-naive patients treated with 6 mg flucizumab compared to 0.3 mg ranibizumab. Results from the off-treatment study observation period provide evidence of a prolonged duration of efficacy with fluvicipizumab compared to anti-VEGF monotherapy. Assessments of time to disease reactivation up to 16 weeks after the last dose demonstrated improved duration of efficacy of flucipirimumab over ranibizumab, as measured by time to loss of ≥ 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and an increase in central retinal thickness (CST) ≥ 50 μm due to DME in a dose-dependent manner in the untreated patient population. This improvement in duration of efficacy of flucipirimumab over ranibizumab was also found in the previously treated cohort and the overall patient population. Based on all of these nonclinical and clinical evidence, treatment with flucipirimumab may produce improved efficacy over the anti-VEGF standard of care in patients with macular edema due to RVO. Furthermore, this study investigated a less frequent treatment dosing schedule (up to every 16 weeks) tailored to individual needs, which could provide comparable BCVA outcomes to more frequent dosing schedules of anti-VEGF monotherapy (e.g., every 4 to 8 weeks). Together, these would represent an important and meaningful advance over currently available therapies. The study design initially evaluated fluvicipizumab, a bispecific antibody that binds to human VEGF and human ANG2 and comprises the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20 (VEGFang2-0016 WO2014 / 009465, incorporated by reference herein, is a Phase III, multicenter, randomized, double-blind, active comparator-controlled, parallel-group study of the efficacy, safety, and pharmacokinetics of this bispecific anti-VEGF / ANG2 antibody (referred to herein as RO6867461 or RG7716 or VEGFang2-0016 or flucipirimumab) in patients with macular edema secondary to / due to CRVO, HRVO, or BRVO, administered by IVT injection at 4-week intervals until Week 24, followed by a double-blind study period without an active control to evaluate flucipirimumab administered according to a PTI dosing regimen. Overview of Study Design This study consists of two parts: Part 1 (Day 1 to Week 24) will compare fluvicepimab Q4W with aflibercept (active comparator) Q4W; Part 2 (Week 24 to Week 72) will evaluate fluvicepimab administered at masked treatment intervals of Q4W to Q16W based on PTI dosing criteria. In Part 1 (Q4W dosing), during the global registration phase of the study, approximately 680 patients will be randomized in a 1:1 ratio to one of two treatment arms, where treatments are defined as follows: - Cohort A (n=340): Patients randomized to Cohort A will receive fluvicipizumab 6 mg IVT Q4W (6 injections) from Day 1 to Week 20. - Cohort B (comparator arm, n=340): Patients randomized to Cohort B will receive aflibercept 2 mg IVT Q4W (6 injections) from Day 1 to Week 20. In Part 2 (PTI regimen), patients in both Cohorts A and B will receive fluvicipizumab 6 mg IVT from Week 24 to Week 68 according to the PTI dosing regimen. All patients will complete Q4W scheduled study visits throughout the study duration (72 weeks). To maintain masking of the flucipirimumab treatment interval from Week 24 to Week 68, sham procedures will be administered during study visits when flucipirimumab treatment (according to the PTI dosing schedule) is not administered. Figure 7 shows an overview of the study design. Only one eye will be designated as the study eye. If both eyes are deemed eligible at the screening assessment, the eye with the worse BCVA will be selected as the study eye, unless the investigator deems the other eye more suitable for the study treatment. A minimum of two investigators will be present at each site to meet the study's masking requirements. At least one investigator will be designated as the assessing physician, who will be masked to each patient's treatment assignment and will evaluate the ocular assessment. At least one other investigator will be unmasked and will administer the study treatment. The study will consist of a screening period of up to 28 days (-28 days to -1 day) and a treatment period of approximately 68 weeks, followed by a final study visit at 72 weeks. Objectives and Endpoints: This study will evaluate the efficacy, safety, and pharmacokinetics of flucipirimumab compared to aflibercept in patients with macular edema secondary to CRVO, HRVO, or BRVO, up to the primary endpoint at Week 24. The efficacy, safety, and pharmacokinetics of flucipirimumab administered according to the PTI dosing schedule (i.e., Q4W to Q16W) will be assessed during the study period from Week 24 to Week 72. The specific objectives and corresponding endpoints of the study are summarized below. In this protocol, "study drug" refers to flucipirimumab or aflibercept, and "study treatment" refers to flucipirimumab, aflibercept, or sham. Efficacy Objectives For efficacy endpoint assessments, BCVA will be assessed on the ETDRS visual acuity chart at an initial testing distance of 4 meters. Primary Efficacy Objectives The primary efficacy objective of this study was to evaluate the efficacy of fluciretomab 6 mg IVT Q4W compared with aflibercept 2 mg IVT Q4W based on the following endpoints: - Change from baseline BCVA at Week 24 Secondary efficacy targets Part of this study 1 ( That is to say, twenty four week ) Of Secondary efficacy objectives were based on the following endpoints: , Efficacy of fluvicipizumab : - Change from baseline BCVA at designated time points up to Week 24 - twenty four - Proportion of patients with a BCVA gain of ≥ 15 letters from baseline at designated time points through Week 24 - Proportion of patients with a BCVA gain of ≥ 15, ≥ 10, ≥ 5, or > 0 letters from baseline at designated time points through Week 24 - Proportion of patients avoiding a BCVA loss of ≥ 15, ≥ 10, ≥ 5, or > 0 letters from baseline at designated time points through Week 24 - Proportion of patients achieving a BCVA ≥ 84 letters (20 / 20 Snellen equivalent) at designated time points through Week 24 - Proportion of patients with a BCVA Snellen equivalent of 20 / 40 or better at designated time points through Week 24 - Proportion of patients with a BCVA Snellen equivalent of 20 / 200 or worse at designated time points through Week 24 - Change from baseline in CST at designated time points through Week 24 - Change from baseline in the National Eye Institute 25-Item Visual Function Questionnaire (NEI) at designated time points through Week 24 Change in VFQ-25 composite score Part of this study 2 ( That is, twenty four week To 72 week ) Of The secondary efficacy objectives were to evaluate the following endpoints: PTI Efficacy of fluciepimumab administered by dosing regimen - Change from baseline in BCVA at designated time points from Week 24 to Week 72 - Proportion of patients with a BCVA gain of ≥ 15 letters from baseline at Week 24 - Proportion of patients with a BCVA gain of ≥ 15, ≥ 10, ≥ 5, or > 0 letters from baseline at designated time points from Week 24 to Week 72 - Proportion of patients who avoided a BCVA loss of ≥ 15, ≥ 10, ≥ 5, or > 0 letters from baseline at designated time points from Week 24 to Week 72 - Proportion of patients who achieved a BCVA ≥ 84 letters (20 / 20 Snellen equivalent) at designated time points from Week 24 to Week 72 - Proportion of patients with a BCVA Snellen equivalent of 20 / 40 or better at designated time points from Week 24 to Week 72 - Proportion of patients with a BCVA of 20 / 200 or worse at designated time points from Week 24 to Week 72 Proportion of patients with Snellen equivalence - Change in BCVA at designated time points from Week 24 to Week 72 - Proportion of patients avoiding BCVA loss of ≥ 15, ≥ 10, ≥ 5, or > 0 letters from Week 24 to Week 72 - Proportion of patients receiving a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W treatment interval at Week 72 - Number of study drug injections received from Week 24 to Week 72 - Change from baseline in CST at designated time points from Week 24 to Week 72 - Change from baseline in NEI VFQ-25 composite score at designated time points from Week 24 to Week 72 Exploratory Efficacy Objectives The exploratory efficacy objectives of this study were to evaluate the efficacy of fluvicipizumab based on the following endpoints: - Proportion of patients with no retinal ischemia on fundus fluorescein angiography (FFA) and optical coherence tomography angiography (OCT-A) (as appropriate) over time (at designated time points) - Change in retinal ischemic area on FFA and OCT-A (as appropriate) from baseline over time - Proportion of patients with vascular leakage on FFA and OCT-A (as appropriate) over time - Change in vascular leakage area on FFA and OCT-A (as appropriate) from baseline over time - Change in foveal avascular zone and other exploratory outputs defined in the SAP (Statistical Analysis Plan) on OCT-A (as appropriate) over time - Proportion of patients with no retinal neovascularization over time (as assessed by the investigator) - Proportion of patients with no vitreous, epiretinal, or subretinal hemorrhage over time (as assessed by the investigator) - Proportion of patients free of anterior segment (iris and angle) neovascularization over time - Proportion of patients requiring panretinal photocoagulation at any time during the study - Proportion of patients free of macular edema (defined as CST ≤ 325 µm for Spectralis SD-OCT or ≤ 315 µm for Cirrus SD-OCT or Topcon SD-OCT) over time - Proportion of patients free of intraretinal fluid over time - Proportion of patients free of subretinal fluid over time - Proportion of patients free of both intraretinal and subretinal fluid over time - Proportion of patients free of intraretinal cysts over time - Change from baseline in NEI VFQ-25 near activity scale scores and distance activity scale scores over time part 1 Treatment Scheduling (Q4W Drug administration ) In Part 1 of the study, patients will receive the following treatment: - Patients randomized to Cohort A will receive fluvicipizumab every 4 weeks from Day 1 to Week 20 - Patients randomized to Cohort B will receive aflibercept every 4 weeks from Day 1 to Week 20 part 2 Of Treatment Scheduling ( Personalized treatment intervals (PTI) plan ) In Part 2 of the study, all patients will visit the clinic Q4W from Week 24 to Week 68 and receive either sham treatment or fluvicipizumab 6 mg IVT, depending on their PTI dosing regimen. Fluciceptin PTI decisions will be automatically calculated based on the PTI criteria described in this section. Study drug dosing interval decisions in the PTI cohort were based on the algorithm described in this section. Fluximab dosing visits were defined as those visits when patients received fluximab 6 mg IVT. Starting at Week 24, patients will receive fluvicipizumab every 4 weeks until their CST meets the pre-defined reference CST threshold (<325 mm for Spectralis SD-OCT, or <315 mm for Cirrus SD-OCT and Topcon SD-OCT), as determined by CRC. The reference CST (as described in Figure 8 and defined below) will be used at the fluvicipizumab dosing visit to determine the fluvicipizumab dosing interval. After determining the patient's initial reference CST, patients will be eligible for increasing the fluvicipizumab dosing interval in 4-week increments (as described in Figure 8 and defined below) if their CST value is stable (i.e., has not increased or decreased by >10%) and there is no associated visual acuity loss of ≥10 letters relative to reference BCVA. Reference CST and reference BCVA (see letters in Figure 8 and in the figure description) a and b ) means the following: a Reference central retinal thickness (CST): The CST value at which the initial CST threshold criteria are met. The reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST between two consecutive study drug dosing visits, and the values ​​obtained are within 30 μm. The CST value obtained at the subsequent visit will serve as the new reference CST, starting immediately at that visit. b Reference best-corrected visual acuity (BCVA): The average of the three best BCVA scores obtained at any previous dosing visit. The maximum and minimum treatment intervals that can be specified will be Q16W and Q4W, respectively. With the exception of patients whose dosing interval is shortened to Q4W, patients who have previously extended their dosing interval and experience disease exacerbation (triggering an interval shortening) will not be allowed to extend their interval again; their interval may be extended again, but only to an interval less than their original maximum extension of 4 weeks. For example, if a patient's interval is shortened from Q12W to Q8W, their interval will not be extended beyond Q8W for the remainder of the treatment period. If a patient's interval is shortened from Q16W to Q4W, their interval may be extended up to Q12W, but not back to Q16W. Flucipirimumab (RO6867461 / RG7716 / VEGFang2-0016) Interval determination The algorithm used for interval decision making is outlined below and in Figure 8 and is based on the relative change in CST and BCVA at the flucipiramumab dosing visit compared to the reference CST and reference BCVA. The flucipiramumab dosing interval will be extended, maintained, or shortened as follows. - In the following cases, Interval extension 4 Increase or decrease in peripheral CST value ≤ 10% without associated BCVA loss ≥ 10 letters - In the event that any of the following criteria are met, interval Maintenance: CST decrease > 10% CST decrease ≤ 10% with associated BCVA decrease ≥ 10 letters CST increase > 10% and ≤ 20% without associated BCVA decrease ≥ 5 letters - In the event that any of the following criteria are met, Shortened interval 4 Week: CST value increase > 10% and ≤ 20% with associated BCVA decrease ≥ 5 to < 10 letters CST value increase > 20% without associated BCVA decrease ≥ 10 letters CST value increase ≤ 10% with associated BCVA decrease ≥ 10 letters - In the following cases, The interval is shortened to Q4WCST value increase > 10% with associated BCVA loss ≥ 10 letters As outlined above, the algorithms used for personalized medication interval decisions are based on the relative change in CST and the absolute change in BCVA compared to reference CST and BCVA, respectively. The algorithm can be implemented by a computing system or device. This computing system or device can include a web interface, a mobile application, a software program, or any clinical decision support tool. For example, a patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing scheduling or notifications, monitor and generate visualizations of dosing interval changes for a given patient, generate visualizations of dosing interval changes for a group of patients, summarize the received CST and BCVA data to determine trends, or a combination thereof. Dosing schedules or notifications may include calendar reminders that display the calendar date for the scheduled dosing visit and notify the clinician or patient of an upcoming dosing visit. Visualizations of dosing interval changes may include, for example, the schematic display in FIG8 . In one instance, a patient's dosing interval adjustment may be displayed in one color, and the patient's immediately previous dosing interval adjustment may be displayed in another color. For example, a patient may first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool may generate a visualization of a patient's personalized interval progression by displaying the "Interval Maintenance" area of ​​the schematic in green and "Interval Extended 4 Weeks" in yellow in FIG8 . Green may reflect the patient's most recent interval calculation and yellow may depict the results of the patient's immediately previous interval calculation. With this visualization, the user of the tool can quickly determine that a patient's disease progression is improving, but not to the extent that their treatment interval can be extended further. The tool can further aggregate patient and dosing schedule data and generate visualizations of the aggregated data. Similar to the color coding example described previously, such data analysis can include visualizations of dosing changes for a single patient. Alternatively, visualizations can display dosing adjustments for a patient group. For example, a visualization can display which patients have interval extensions and which patients have interval shortenings. This visualization can be organized by various features, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, etc. The tool can also aggregate patient CST and BCVA data and generate visualizations based on the data. Visualizations can display trends in data to facilitate or generate longitudinal analysis. These visualizations can include reminders, curves, analysis workflow interfaces, or any graphical interfaces. The tool can generate a dosing schedule output or visualization in response to or in conjunction with the ocular assessment and images. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture ocular images. The tool can further employ image segmentation, image recognition, or machine learning techniques to calculate CST based on ocular images. Regarding BCVA, the tool can virtually manage ocular assessments, prompting and collecting patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track ocular assessment data. In this way, the tool can track disease progression for each patient and adjust the dosing schedule accordingly. Embodiments of the present invention may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, the method comprising: receiving patient data at a computing system, the patient data comprising the patient's CST and best-corrected visual acuity (BCVA); using the computing system to extend, shorten, or maintain a dosing interval based on the received patient data compared to respective reference CST and BCVA; and obtaining a PTI based on the dosing interval. An exemplary dosing interval is extended by four weeks in the event of an increase or decrease in CST value of ≤ 10% without an associated decrease in BCVA of ≥ 10 letters. The exemplary dosing interval is maintained if any of the following criteria are met: a decrease in CST value of >10%; or a decrease in CST value of ≤10% with an associated decrease in BCVA of ≥10 letters, or an increase in CST value of >10% and ≤20% without an associated decrease in BCVA of ≥5 letters. The exemplary dosing interval is shortened to 4 weeks if any of the following criteria are met: an increase in CST value of >10% and ≤20% with an associated decrease in BCVA of ≥5 to <10 letters, or an increase in CST value of >20% without an associated decrease in BCVA of ≥10 letters; or an increase in CST value of ≤10% with an associated decrease in BCVA of ≥10 letters. In the case of an increase in CST value of >10% with an associated decrease in BCVA of ≥10 letters, the exemplary dosing interval is shortened to Q4W. This method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from an ocular vascular disease selected from macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion may further include receiving updated patient data at a computing system; continuously updating or maintaining the dosing interval based on the updated patient data using the computing system; and generating a visualization, user interface, or notification based on the updated or maintained dosing interval. Embodiments of the present invention also include the use of a personalized dosing schedule based on a personalized treatment interval (PTI) for treating macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion, or secondary to branch vein occlusion, wherein a computing system obtains the PTI by receiving patient data including the patient's CST and best-corrected visual acuity (BCVA) and, based on the received patient data compared to respective reference CST and BCVA, extending, shortening, or maintaining the dosing interval. An exemplary dosing interval is extended by 4 weeks if the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters. An exemplary dosing interval is maintained if any of the following criteria are met: a decrease in CST value of > 10%; or a decrease in CST value of ≤ 10% with an associated BCVA decrease of ≥ 10 letters; or an increase in CST value of > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters. The exemplary dosing interval is shortened to 4 weeks if any of the following criteria are met: CST value increase > 10% and ≤ 20%, with an associated BCVA decrease of ≥ 5 to < 10 letters, or CST value increase > 20% without an associated BCVA decrease of ≥ 10 letters; or CST value increase ≤ 10%, with an associated BCVA decrease of ≥ 10 letters. In the case of a CST value increase > 10%, with an associated BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened to Q4W. Eye Review Unless otherwise indicated, ocular assessments will be performed on both eyes at designated time points according to the active schedule. Assessments will include: - Refraction and BCVA assessed on the ETDRS visual acuity chart at a starting testing distance of 4 meters (performed before the eye is expanded) - Pre-dose IOP measurement in both eyes (performed before the eye is expanded) - Slit lamp examination (for grading of anterior muscle and vitreous cells) - Dilated binocular indirect high-power ophthalmoscopy - Finger counting test, followed by hand movements and light perception testing (if needed) performed approximately 15 minutes after study treatment in the study eye - Post-dose IOP (intraocular pressure) measurement in the study eye only, 30 (±15) minutes after study treatment administration If there are no safety concerns 30 (±15) minutes after study treatment administration, the patient will be discharged from the clinic. If the IOP value is of concern to the treating administrator / unblinded investigator, the patient will remain in the clinic and will be managed according to the clinical judgment of the treating administrator / unblinded investigator. When appropriate, adverse events will be recorded on the electronic case report form (eCRF). - The IOP measurement method used for the patient must remain constant throughout the study ocular imaging. After randomization, if a patient missed a study visit when color fundus photography (CFP) or fundus fluorescein angiography (FFA) ocular imaging was scheduled or images were not obtained at the scheduled visit (e.g., because of broken equipment), images were obtained at the next scheduled visit in which the patient attended. Eye imaging includes the following: : - FFA of the study eye - CFP of the study eye - Spectral domain optical coherence tomography (SD-OCT) or swept source OCT (SS-OCT) images of the study eye - Optional OCT-A of the study eye at a site with OCT-A capabilities (provided site-approved optional sampling) For patients diagnosed with bilateral RVO at screening, CFP and OCT images of the other eye will also be captured and stored at the CRC. Results The primary efficacy analysis included all randomized patients, with patients assigned according to randomized treatment. The primary efficacy variable is the change in BCVA.The primary efficacy analysis will be performed using, for example, a mixed model with repeated measurements model (MMRM). Best-corrected visual acuity (BCVA) was measured as described. The primary efficacy outcome measure is shown in the graph showing the primary efficacy endpoint: change in patient BCVA over time relative to baseline. The bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, was compared according to the study protocol described above (administered intravitreally at 6.0 mg as described in Cohort A using personalized treatment intervals) to Cohort B (aflibercept (Eylea®) in Part 1 of the study). Central macular retinal thickness relative to baseline (CST) of change ( Studying the Eyes The key secondary endpoint was the change in CST (central macular retinal thickness) from baseline. CST (and retinal thickness) was measured by optical coherence tomography (OCT). The results are shown in a figure showing the change in CST over time for the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab), comprising the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, administered intravitreally at 6.0 mg as described in Cohort A using a personalized treatment interval, compared to, for example, Cohort B (aflibercept (Eylea®) in Part 1 of the study), according to the study protocol described above. Other results of eye assessment and imaging can therefore be displayed. Example 4 Binding of Anti-VEGF / ANG2 Antibodies to VEGF, Ang2, FcγR, and FcRn VEGF isoform kinetic affinity, including species cross-reactivity, was assessed by coupling the capture system (10 μg / ml goat anti-human F(ab)) to a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 using an amine coupling kit supplied by GE Healthcare. 2; order code: 28958325; GE Healthcare Bio-Sciences AB, Sweden) with approximately 12,000 resonance units (RU). The sample and system buffer was PBS-T (10 mM phosphate-buffered saline, including 0.05% Tween® 20), pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C and pre-coated twice with running buffer. The bispecific antibody was captured by injecting a 50 nM solution at a flow rate of 5 µl / min for 30 seconds. Association was measured by injecting human hVEGF121, mouse mVEGF120, or rat rVEGF164 at various concentrations in solution, starting at 300 nM in a 1:3 dilution, at a flow rate of 30 µl / min for 300 seconds. The dissociation phase was monitored for up to 1200 seconds and triggered by switching from the sample solution to the running buffer. The surface was regenerated by washing with glycine pH 2.1 for 60 seconds at a flow rate of 30 μl / min. The responses obtained from the two surfaces were used to correct for overall refractive index differences. A blank injection (= secondary reference) was also subtracted. To calculate the apparent K D The Langmuir 1:1 model was used for the kinetic parameters and the results are shown in Table 5. Ang2 Solution Affinity, Including Assessment of Species Cross-Reactivity: Solution affinity measures the affinity of the interaction by determining the concentration of the free interacting partner in the equilibrium mixture. Solution affinity analysis involves mixing the <VEGF-ANG-2> bispecific antibody (maintained at a constant concentration) with varying concentrations of the ligand (=Ang2). The maximum possible resonance units (e.g., 17,000 resonance units (RU)) of the antibody are immobilized on a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 using an amine coupling kit supplied by GE Healthcare. The sample and system buffer is HBS-P pH 7.4. The flow cell is set to 25°C, and the sample block is set to 12°C and pre-coated twice with running buffer. To generate a calibration curve, increasing concentrations of Ang2 are injected into the BIAcore™ flow cell containing the immobilized VEGF-ANG-2> bispecific antibody. The amount of bound Ang2 is determined in resonance units (RU) and plotted against concentration. Solutions of each ligand (11 concentrations ranging from 0 to 200 nM for the VEGF-ANG-2> bispecific antibody) were incubated with 10 nM Ang2 and allowed to equilibrate at room temperature. Free Ang2 concentrations were determined based on a calibration curve generated before and after the reaction with solutions containing known amounts of Ang2. A four-parameter fit was set using model 201, with free Ang2 concentration as the y-axis and inhibitory antibody concentration as the x-axis, using XLfit4 (IDBS software). Affinity was calculated by determining the inflection point of this curve. 3PO The surface was regenerated by washing once for 30 seconds with 4% HCl at a flow rate of 30 μl / min. Overall refractive index differences were corrected by subtracting the response obtained from a blank coupled surface. The results are shown in the table below. FcRn Steady-State Affinity: For FcRn measurements, steady-state affinity was used to compare bispecific antibodies. Human FcRn was diluted in coupling buffer (10 µg / ml, sodium acetate, pH 5.0) and immobilized on a C1 chip (GE Healthcare BR-1005-35) using the targeted immobilization procedure using BIAcore™ to a final reaction of 200 RU. The flow cell was set to 25°C, and the sample block was set to 12°C and pre-coated twice with running buffer. The sample and system buffer was PBS-T (10 mM phosphate-buffered saline, including 0.05% Tween® 20), pH 6.0. To evaluate different IgG concentrations of each antibody, concentrations of 62.5 nM, 125 nM, 250 nM, and 500 nM were prepared. The flow rate was set to 30 µl / min, and different samples were continuously injected onto the chip surface, with an association time of 180 seconds. The surface was regenerated by injecting PBS-T pH 8 for 60 seconds at a flow rate of 30 μl / min. The overall refractive index difference was corrected by subtracting the reaction obtained from the blank surface. Buffer injection (= secondary reference) was also subtracted. To calculate steady-state affinity, a method according to Bia-Evaluation software was used. In brief, RU values ​​(RU maximum) were plotted relative to the assay concentration to obtain a dose-response curve. Based on a 2-parameter fit, the upper asymptote was calculated, allowing the determination of half-maximum RU values, and thus affinity was determined. The results are shown in the table below. Similarly, affinity for cynomolgus macaques, mice, and rabbit FcRn can be determined. FcγRIIIa Measurement: For FcγRIIIa measurement, a direct binding assay was used. Approximately 3,000 resonance units (RU) of the capture system (1 µg / ml Penta-His; Qiagen) were coupled to a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 using an amine coupling kit supplied by GE Healthcare. The sample and system buffer was HBS-P+, pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C and pre-coated twice with running buffer. FcγRIIIa-His-antibody was captured by injecting a 100 nM solution at a flow rate of 5 µl / min for 60 seconds. Binding was measured by injecting a 100 nM bispecific antibody or a monospecific control antibody (anti-Dig of the IgG1 and IgG4 subclasses) at a flow rate of 30 µl / min for 180 seconds. The surface was regenerated by washing with glycine pH 2.5 for 120 seconds at a flow rate of 30 μl / min. Because FcγRIIIa binding differs from the Langmuir 1:1 model, only binding / absence was determined using this assay. FcγRIa and FcγRIIa binding can be determined in a similar manner. The results are shown in the table below, where subsequent introduction of the mutation P329G LALA reduced FcγRIIIa binding to undetectable levels. Binding of independent VEGF and Ang2 to the <VEGF-ANG-2> bispecific antibody was assessed by coupling a capture system (10 µg / ml goat anti-human IgG; GE Healthcare Bio-Sciences AB, Sweden) at approximately 3500 resonance units (RU) to a CM4 chip (GE Healthcare BR-1005-34) using an amine coupling kit supplied by GE Healthcare at pH 5.0. The sample and system buffer was PBS-T (10 mM phosphate-buffered saline containing 0.05% Tween® 20) at pH 7.4. The flow cell temperature was set to 25°C, and the sample block temperature was set to 12°C. Prior to capture, the flow cell was pre-coated twice with running buffer. The bispecific antibody was captured by injecting a 10 nM solution for 60 seconds at a flow rate of 5 µl / min. The independent binding of each ligand to the bispecific antibody was analyzed by measuring the active binding capacity of each ligand added sequentially or simultaneously (flow rate of 30 µl / min): 1. Injection of human VEGF at a concentration of 200 nM for 180 seconds (to identify single binding of the antigen). 2. Injection of human Ang2 at a concentration of 100 nM for 180 seconds (to identify single binding of the antigen). 3. Injection of human VEGF at a concentration of 200 nM for 180 seconds, followed by an injection of human Ang2 at a concentration of 100 nM for 180 seconds (to identify binding of Ang2 in the presence of VEGF). 4. Injection of human Ang2 at a concentration of 100 nM for 180 seconds, followed by an injection of human VEGF at a concentration of 200 nM (to identify binding of VEGF in the presence of Ang2). 5. Human VEGF at a concentration of 200 nM and human Ang2 at a concentration of 100 nM were co-injected for 180 seconds (to identify the binding of VEGF and Ang2 simultaneously). At a flow rate of 30 µl / min, 3 mM MgCl The surface was regenerated by washing with solution 2 for 60 seconds. The overall refractive index difference was corrected by subtracting the response obtained from the goat anti-human IgG surface. If the final signal obtained from methods 3, 4, and 5 is equal to or similar to the sum of the individual final signals from methods 1 and 2, the bispecific antibody is capable of binding to both antigens independently of one another. The results are shown in the table below, which demonstrates that VEGFang2-0016 (= RO6867461) is capable of binding independently of one another to VEGF and ANG2. Simultaneous binding of VEGF and Ang2 to the <VEGF-ANG-2> bispecific antibody was assessed. First, approximately 1600 resonance units (RU) of VEGF (20 µg / ml) were coupled to a CM4 chip (GE Healthcare BR-1005-34) at pH 5.0 using an amine coupling kit supplied by GE Healthcare. The sample and system buffer was PBS-T (10 mM phosphate-buffered saline containing 0.05% Tween® 20) at pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C and pre-coated twice with running buffer. Next, a 50 nM solution of the bispecific antibody was injected at a flow rate of 30 µl / min for 180 seconds. Third, hAng-2 was injected at a flow rate of 30 µl / min for 180 seconds. The hAng-2 binding response was dependent on the amount of bispecific antibody bound to VEGF and demonstrated simultaneous binding. The slurry was washed with 0.85% H 3PO The surface was regenerated by washing with 4% ... Table: Results: Solution affinity for Ang2 Table: Results: Affinity of <VEGF-ANG-2> bispecific antibody for FcRn Table: Results: Binding to FcγIIIa Table: Results: Independent binding of VEGF and Ang2 to the <VEGF-ANG-2> bispecific antibody picture 1 Figure 1 shows an overview of the study design for nAMD. a Patients will undergo disease activity assessments at Weeks 20 and 24. Patients with anatomical or functional signs of disease activity at these time points will receive dosing every 8 weeks or every 12 weeks, respectively, rather than every 16 weeks. b The primary endpoint is the change from baseline in BCVA (as assessed on the ETDRS chart at a 4-meter starting distance) based on the mean values ​​at Weeks 40, 44, and 48. c Beginning at Week 60 (when all patients in Cohort A are scheduled to receive faricimab), patients in Cohort A will be treated according to the PTI dosing schedule (between every 8 weeks and every 16 weeks). BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; IVT = intravitreal; PTI = personalized treatment interval; Q8W = every 8 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; W = week. picture 2 Figure 2 shows an overview of the study design for DME. Cohort A (Q8W dosing): Patients randomized to Cohort A will receive Q4W 6-mg IVT RO6867461 (flucipirimumab) injections until Week 20, followed by Q8W 6-mg IVT RO6867461 (flucipirimumab) injections until Week 96, followed by the final study visit at Week 100. Cohort B (Personalized Treatment Interval (PTI)): Patients randomized to Cohort B will receive Q4W 6-mg IVT RO6867461 (flucipirimumab) injections until at least Week 12, followed by PTI dosing of 6-mg IVT RO6867461 (flucipirimumab) injections (see PTI dosing guidelines below) until Week 96, followed by the final study visit at Week 100. Cohort C (Comparator Cohort) (Q8W Dosing): Patients randomized to Cohort C will receive 2-mg IVT aflibercept injections Q4W through Week 16, followed by 2-mg IVT aflibercept injections Q8W through Week 96, followed by the final study visit at Week 100. Patients in all three treatment arms will complete the Q4W scheduled study visits for the entire duration of the study (100 weeks). Patients in all three treatment arms will receive a sham procedure at applicable visits to maintain masking between treatment arms. IVT = intravitreal; Q8W = every 8 weeks; PTI = personalized treatment interval (see Section 3.1.2 for additional details); W = week. a The 1-year definition for the primary efficacy endpoint (defined as the change from baseline in BCVA as measured on the ETDRS chart at a 4-meter starting distance at 1 year) was the mean of the Week 48, Week 52, and Week 56 visits. picture 3 : Schematic personalized treatment interval for DME - Figure 3 summarizes the algorithm used for interval decision-making, which is based on the relative change in CST and BCVA compared to the reference CST and reference BCVA. The meaning of * and ** in Figure 3: *Reference central retinal thickness (CST): The CST value at which the initial CST threshold criteria are met. The reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST between two consecutive study drug dosing visits, and the values ​​obtained are within 30 μm. The CST value obtained at the subsequent visit will serve as the new reference CST, starting immediately at that visit. **Reference best-corrected visual acuity (BCVA): The average of the three best BCVA scores obtained at any previous dosing visit. picture 4 : Schematic comparison of durability (time to retreatment) and efficacy (DME) in DME and nAMD based on published results with other treatment options for DME and nAMD (comparative agents Lucentis® (ranbizumab), Eylea® (aflibercept), brolucizumab, and VA2 (RO6867461 / flucipizumab)). picture 5 : Gain from baseline in BCVA in patients with neovascular age-related macular degeneration (nAMD) comparing the bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab) at 12 and 16 week intervals with ranibizumab (Lucentis®) at 4 week intervals. picture 6 Time to retreatment for diabetic macular edema (DME) based on disease activity, assessed by both a BCVA loss of ≥ 5 letters and a CST gain of ≥ 50 µm after dosing has ceased (after 20 weeks or 6-monthly dosing = time since most recent intravitreal (IVT) administration). The bispecific anti-VEGF / ANG2 antibody RO6867461 (flucipirimumab) was compared to ranibizumab (Lucentis®) and demonstrated a longer time to retreatment. picture 7 : Figure 7 shows an overview of the study design for the treatment of macular edema secondary to retinal vein occlusion (RVO). IVT = intravitreal; PTI = personalized treatment interval; Q4W = every 4 weeks; W = week. picture 8 Schematic personalized treatment intervals for the treatment of macular edema secondary to retinal vein occlusion (RVO) - Figure 8 outlines the algorithm used for interval decisions, which is based on relative changes in CST and BCVA compared to the reference CST and reference BCVA. BCVA = best-corrected visual acuity; CST = central retinal thickness of the macula; Q4W = every 4 weeks. a Initial reference CST = CST value at the time the initial CST threshold criteria are met, but no earlier than Week 20. The reference CST is adjusted if the CST decreases by >10% relative to the previous reference CST at two consecutive fluvicipizumab dosing visits, and the values ​​obtained are within 30 µm. The CST value obtained at the subsequent visit serves as the new reference CST, starting immediately at that visit. b Reference BCVA = the average of the three best BCVA scores obtained at any previous dosing visit. <![CDATA[ <110> F. Hoffman-La Roche AG Genentech Inc. <![CDATA[ <120> Personalized treatment of eye diseases]]> <![CDATA[ <150> US 62 / 883,499 <![CDATA[ <151> 2019-08-06 <![CDATA[ <160> 27 ]]> <![CDATA[ <170> PatentIn version 3.5 <![CDATA[ <210> 1]]> <![CDATA[ <211> 14]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain CDR3H, <vegf>Ranibizumab <![CDATA[ <400> 1]]> Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 1 5 10 <![CDATA[ <210> 2]]> <![CDATA[ <211> 17]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[<223]]> > Heavy chain CDR2H, <vegf>Ranibizumab <![CDATA[ <400> 2]]> <![CDATA[Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 1 5 10 15 Arg <![CDATA[ <210> 3]]> <![CDATA[ <211> 5]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain CDR1H, <vegf>Ranibizumab <![CDATA[ <400> 3]]> His Tyr Gly Met Asn 1 5 <![CDATA[ <210> 4]]> <![CDATA[ <211> 9]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR3L, <vegf>Ranibizumab <![CDATA[ <400> 4]]> Gln Gln Tyr Ser Thr Val Pro Trp Thr 1 5 <![CDATA[ <210> 5]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR2L, <vegf>Ranibizumab <![CDATA[ <400> 5]]> Phe Thr Ser Ser Leu His Ser 1 5 <![CDATA[ <210> 6]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR1L, ]]> <![CDATA[ <vegf>Ranibizumab <![CDATA[ <400> 6]]> Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <![CDATA[ <210> 7]]> <![CDATA[ <211> 123]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain variable domain VH, <vegf>Lambizumab monoclonal antibody <![CDATA[<400> 7]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 8]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain variable domain VL, <vegf>Lambizumab monoclonal antibody]]> <![CDATA[<400> 8]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 9]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial]]> <![CDATA[<220>]]> <![CDATA[<223> Heavy chain CDR3H, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> 9]]> Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Pro Gly 1 5 10 15 Ala Phe Asp Ile 20 <![CDATA[ <210> 10]]> <![CDATA[ <211> 17]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain CDR2H, <ang-2>Ang2i_LC10 variant <![CDATA[ <400> 10]]> Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[ <210> 11]]> <![CDATA[ <211> 5]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain CDR1H, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> 11]]> Gly Tyr Tyr Met His 1 5 <![CDATA[ <210> 12]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR3L, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> ]]> 12 Gln Val Trp Asp Ser Ser Ser Asp His Trp Val 1 5 10 <![CDATA[ <210> 13]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR2L, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> 13]]> Asp Asp Ser Asp Arg Pro Ser 1 5 <![CDATA[ <210> 14]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain CDR1L, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> 14]]> Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His 1 5 10 <![CDATA[ <210> 15]]> <![CDATA[ <211> 129]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Heavy chain variable domain VH, <ang-2>Ang2i_LC10 variant <![CDATA[<400> 15]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr 100 105 110 Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 115 120 125 Ser <![CDATA[<210> 16]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain variable domain VL, <ang-2>Ang2i_LC10 variant]]> <![CDATA[ <400> 16]]> Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr 35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95 Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser Ser 100 105 110 <![CDATA[ <210> 17]]> <![CDATA[ <211> 451]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> With AAA mutation and P329G LALA mutation <vegf-ang-2>CrossMAb IgG1]]> Heavy chain 1 of (VEGFang2-0016) <![CDATA[<400> 17]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 225 230 235 240 Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255 Leu Met Ala Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu Ala Gln Asp Trp Leu 305 310 315 320 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala 325 330 335 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350 Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln 355 360 365 Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430 Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser 435 440 445 Leu Ser Pro 450 <![CDATA[ <210> 18]]> <![CDATA[ <211> 461]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> With AAA mutation and P329G LALA mutation <vegf-ang-2>CrossMAb IgG1]]> Heavy chain 2 of (VEGFang2-0016) <![CDATA[<400> 18]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr 100 105 110 Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 115 120 125 Ser Ala Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Lys Thr His 225 230 235 240 Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 245 250 255 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ala Ser Arg Thr 260 265 270 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 275 280 285 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Leu Ala Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 355 360 365 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 370 375 380 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435 440 445 His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460 <![CDATA[ <210> 19]]> <![CDATA[ <211> 214]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> With AAA mutation and P329G LALA mutation <vegf-ang-2>CrossMAb IgG1 ]]> Light chain 1 of (VEGFang2-0016) <![CDATA[<400> 19]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Note: There seems to be a minor error in the original text where "95" is written as "90" in line 28. This has been corrected in the translation.130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[ <210> 20]]> <![CDATA[ <211> 213]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Manual]]> <![CDATA[ <220> ]]> <![CDATA[ <223> With AAA mutation and P329G LALA mutation <vegf-ang-2>CrossMAb IgG1 ]]> Light chain 2 of (VEGFang2-0016) <![CDATA[<400> 20]]> Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr 35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95 Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser Ser Ala Ser 100 105 110 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 115 120 125 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 130 135 140 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 145 150 155 160 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 165 170 175 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 180 185 190 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 195 200 205 Glu Pro Lys Ser Cys 210 <![CDATA[<210> 21]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 21]]> Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 [[ID=]] Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 22]]> <![CDATA[<211> 105]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 22]]> Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu [[ID=-27]] 1 5 10 15 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 20 25 30 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 35 40 45 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 50 55 60 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 65 70 75 80 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 85 90 95 Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <![CDATA[<210> 23]]> <![CDATA[<211> 328]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 23]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro 325 <![CDATA[<210> 24]]> <![CDATA[<211> 191]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 24]]> Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu 1 5 10 15 Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly 20 25 30 Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln 35 40 45 Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu 50 55 60 Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu 65 70 75 80 Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro 85 90 95 Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His 100 105 110 Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys 115 120 125 Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Asn Pro Cys Gly 130 135 140 Pro Cys Ser Glu Arg Arg Lys His Leu Phe Val Gln Asp Pro Gln Thr 145 150 155 160 Cys Lys Cys Ser Cys Lys Asn Thr Asp Ser Arg Cys Lys Ala Arg Gln 165 170 175 Leu Glu Leu Asn Glu Arg Thr Cys Arg Cys Asp Lys Pro Arg Arg 180 185 190 <![CDATA[<210> 25]]> <![CDATA[<211> 496]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 25]]> Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala 1 5 10 15 Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys 20 25 30 <![CDATA[ ]] Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro 35 40 45 Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala 50 55 60 Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu 65 70 75 80 Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys 85 90 95 Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile 100 105 110 Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly 115 120 125 Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp 130 135 140 Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu 145 150 155 160 Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp 165 170 175 Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu 180 185 190 Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser 195 200 205 Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn 210 215 220 Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn 225 230 235 240 Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn 245 250 255 Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr 260 265 270 Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe 275 280 285 Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn 290 295 300 Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly 305 310 315 320 Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln 325 330 335 Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu 340 345 350 Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg 355 360 365 Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr 370 375 380 Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg 385 390 395 400 Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile 405 410 415 Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys 420 425 430 Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp 435 440 445 Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln 450 455 460 Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser 465 470 475 480 Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe 485 490 495 <![CDATA[<210]]>> 26]]> <![CDATA[<211> 498]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 26]]> <![CDATA[Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His 1 5 10 15 Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg 20 25 30 Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro 35 40 45 Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr 50 55 60 Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser 65 70 75 80 Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp 85 90 95 Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met 100 105 110 Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu 115 120 125 Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys 130 135 140 Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu 145 150 155 160 Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln 165 170 175 Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser 180 185 190 Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu 195 200 205 Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr 210 215 220 Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala 225 230 235 240 Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp 245 250 255 Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu 260 265 270 Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp 275 280 285 Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile 290 295 300 Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn 305 310 315 320 Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp 325 330 335 Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser 340 345 350 Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln 355 360 365 Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg 370 375 380 Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn 385 390 395 400 Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser 405 410 415 Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn 420 425 430 Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp 435 440 445 Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala 450 455 460 Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys 465 470 475 480 Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu 485 490 495 Asp Phe <![CDATA[<210> 27]]> <![CDATA[<211> 1124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Homo sapiens]]> <![CDATA[<400> 27]]> Met Asp Ser Leu Ala Ser Leu Val Leu Cys Gly Val Ser Leu Leu Leu 1 5 10 15 Ser Gly Thr Val Glu Gly Ala Met Asp Leu Ile Leu Ile Asn Ser Leu 20 25 30 Pro Leu Val Ser Asp Ala Glu Thr Ser Leu Thr Cys Ile Ala Ser Gly 35 40 45 Trp Arg Pro His Glu Pro Ile Thr Ile Gly Arg Asp Phe Glu Ala Leu 50 55 60 Met Asn Gln His Gln Asp Pro Leu Glu Val Thr Gln Asp Val Thr Arg 65 70 75 80 Glu Trp Ala Lys Lys Val Val Trp Lys Arg Glu Lys Ala Ser Lys Ile 85 90 95 Asn Gly Ala Tyr Phe Cys Glu Gly Arg Val Arg Gly Glu Ala Ile Arg 100 105 110 Ile Arg Thr Met Lys Met Arg Gln Gln Ala Ser Phe Leu Pro Ala Thr 115 120 125 Leu Thr Met Thr Val Asp Lys Gly Asp Asn Val Asn Ile Ser Phe Lys 130 135 140 Lys Val Leu Ile Lys Glu Glu Asp Ala Val Ile Tyr Lys Asn Gly Ser 145 150 155 160 Phe Ile His Ser Val Pro Arg His Glu Val Pro Asp Ile Leu Glu Val 165 170 175 His Leu Pro His Ala Gln Pro Gln Asp Ala Gly Val Tyr Ser Ala Arg 180 185 190 Tyr Ile Gly Gly Asn Leu Phe Thr Ser Ala Phe Thr Arg Leu Ile Val 195 200 205 Arg Arg Cys Glu Ala Gln Lys Trp Gly Pro Glu Cys Asn His Leu Cys 210 215 220 Thr Ala Cys Met Asn Asn Gly Val Cys His Glu Asp Thr Gly Glu Cys 225 230 235 240 Ile Cys Pro Pro Gly Phe Met Gly Arg Thr Cys Glu Lys Ala Cys Glu 245 250 255 Leu His Thr Phe Gly Arg Thr Cys Lys Glu Arg Cys Ser Gly Gln Glu 260 265 270 Gly Cys Lys Ser Tyr Val Phe Cys Leu Pro Asp Pro Tyr Gly Cys Ser 275 280 285 Cys Ala Thr Gly Trp Lys Gly Leu Gln Cys Asn Glu Ala Cys His Pro 290 295 300 Gly Phe Tyr Gly Pro Asp Cys Lys Leu Arg Cys Ser Cys Asn Asn Gly 305 310 315 320 Glu Met Cys Asp Arg Phe Gln Gly Cys Leu Cys Ser Pro Gly Trp Gln 325 330 335 Gly Leu Gln Cys Glu Arg Glu Gly Ile Pro Arg Met Thr Pro Lys Ile 340 345 350 Val Asp Leu Pro Asp His Ile Glu Val Asn Ser Gly Lys Phe Asn Pro 355 360 365 Ile Cys Lys Ala Ser Gly Trp Pro Leu Pro Thr Asn Glu Glu Met Thr 370 375 380 Leu Val Lys Pro Asp Gly Thr Val Leu His Pro Lys Asp Phe Asn His 385 390 395 400 Thr Asp His Phe Ser Val Ala Ile Phe Thr Ile His Arg Ile Leu Pro 405 410 415 Pro Asp Ser Gly Val Trp Val Cys Ser Val Asn Thr Val Ala Gly Met 420 425 430 Val Glu Lys Pro Phe Asn Ile Ser Val Lys Val Leu Pro Lys Pro Leu 435 440 445 Asn Ala Pro Asn Val Ile Asp Thr Gly His Asn Phe Ala Val Ile Asn 450 455 460 Ile Ser Ser Glu Pro Tyr Phe Gly Asp Gly Pro Ile Lys Ser Lys Lys 465 470 475 480 Leu Leu Tyr Lys Pro Val Asn His Tyr Glu Ala Trp Gln His Ile Gln 485 490 495 Val Thr Asn Glu Ile Val Thr Leu Asn Tyr Leu Glu Pro Arg Thr Glu 500 505 510 Tyr Glu Leu Cys Val Gln Leu Val Arg Arg Gly Glu Gly Gly Glu Gly 515 520 525 His Pro Gly Pro Val Arg Arg Phe Thr Thr Ala Ser Ile Gly Leu Pro 530 535 540 Pro Pro Arg Gly Leu Asn Leu Leu Pro Lys Ser Gln Thr Thr Leu Asn 545 550 555 560 Leu Thr Trp Gln Pro Ile Phe Pro Ser Ser Glu Asp Asp Phe Tyr Val 565 570 575 Glu Val Glu Arg Arg Ser Val Gln Lys Ser Asp Gln Gln Asn Ile Lys 580 585 590 Val Pro Gly Asn Leu Thr Ser Val Leu Leu Asn Asn Leu His Pro Arg 595 600 605 Glu Gln Tyr Val Val Arg Ala Arg Val Asn Thr Lys Ala Gln Gly Glu 610 615 620 Trp Ser Glu Asp Leu Thr Ala Trp Thr Leu Ser Asp Ile Leu Pro Pro 625 630 635 640 Gln Pro Glu Asn Ile Lys Ile Ser Asn Ile Thr His Ser Ser Ala Val 645 650 655 Ile Ser Trp Thr Ile Leu Asp Gly Tyr Ser Ile Ser Ser Ile Thr Ile 660 665 670 Arg Tyr Lys Val Gln Gly Lys Asn Glu Asp Gln His Val Asp Val Lys 675 680 685 Ile Lys Asn Ala Thr Ile Thr Gln Tyr Gln Leu Lys Gly Leu Glu Pro 690 695 700 Glu Thr Ala Tyr Gln Val Asp Ile Phe Ala Glu Asn Asn Ile Gly Ser 705 710 715 720 Ser Asn Pro Ala Phe Ser His Glu Leu Val Thr Leu Pro Glu Ser Gln 725 730 735 Ala Pro Ala Asp Leu Gly Gly Gly Lys Met Leu Leu Ile Ala Ile Leu 740 745 750 Gly Ser Ala Gly Met Thr Cys Leu Thr Val Leu Leu Ala Phe Leu Ile 755 760 765 Ile Leu Gln Leu Lys Arg Ala Asn Val Gln Arg Arg Met Ala Gln Ala 770 775 780 Phe Gln Asn Val Arg Glu Glu Pro Ala Val Gln Phe Asn Ser Gly Thr 785 790 795 800 Leu Ala Leu Asn Arg Lys Val Lys Asn Asn Pro Asp Pro Thr Ile Tyr 805 810 815 Pro Val Leu Asp Trp Asn Asp Ile Lys Phe Gln Asp Val Ile Gly Glu 820 825 830 Gly Asn Phe Gly Gln Val Leu Lys Ala Arg Ile Lys Lys Asp Gly Leu 835 840 845 Arg Met Asp Ala Ala Ile Lys Arg Met Lys Glu Tyr Ala Ser Lys Asp 850 855 860 Asp His Arg Asp Phe Ala Gly Glu Leu Glu Val Leu Cys Lys Leu Gly 865 870 875 880 His His Pro Asn Ile Ile Asn Leu Leu Gly Ala Cys Glu His Arg Gly 885 890 895 Tyr Leu Tyr Leu Ala Ile Glu Tyr Ala Pro His Gly Asn Leu Leu Asp 900 905 910 Phe Leu Arg Lys Ser Arg Val Leu Glu Thr Asp Pro Ala Phe Ala Ile 915 920 925 Ala Asn Ser Thr Ala Ser Thr Leu Ser Ser Gln Gln Leu Leu His Phe 930 935 940 Ala Ala Asp Val Ala Arg Gly Met Asp Tyr Leu Ser Gln Lys Gln Phe 945 950 955 960 Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn Tyr 965 970 975 Val Ala Lys Ile Ala Asp Phe Gly Leu Ser Arg Gly Gln Glu Val Tyr 980 985 990 Val Lys Lys Thr Met Gly Arg Leu Pro Val Arg Trp Met Ala Ile Glu 995 1000 1005 Ser Leu Asn Tyr Ser Val Tyr Thr Thr Asn Ser Asp Val Trp Ser 1010 1015 1020 Tyr Gly Val Leu Leu Trp Glu Ile Val Ser Leu Gly Gly Thr Pro 1025 1030 1035 Tyr Cys Gly Met Thr Cys Ala Glu Leu Tyr Glu Lys Leu Pro Gln 1040 1045 1050 Gly Tyr Arg Leu Glu Lys Pro Leu Asn Cys Asp Asp Glu Val Tyr 1055 1060 1065 Asp Leu Met Arg Gln Cys Trp Arg Glu Lys Pro Tyr Glu Arg Pro 1070 1075 1080 Ser Phe Ala Gln Ile Leu Val Ser Leu Asn Arg Met Leu Glu Glu 1085 1090 1095 Arg Lys Thr Tyr Val Asn Thr Thr Leu Tyr Glu Lys Phe Thr Tyr 1100 1105 1110 Ala Gly Ile Asp Cys Ser Ala Glu Glu Ala Ala 1115 1120 < / vegf> < / vegf> < / vegf> < / vegf> < / vegf> < / vegf> < / vegf> < / vegf>

Claims

1. The use of faricimab for the treatment of patients with ocular vascular diseases selected from those secondary to central retinal vein occlusion, hemiretinal vein occlusion, or branch vein occlusion, wherein the treatment comprises a personalized treatment interval (PTI), wherein a) the patient is initially treated with faricimab every 4 weeks (Q4W) from day 1 to week 20, wherein faricimab is administered at a dose of approximately 6 mg; b) from week 24, the patient is treated with faricimab at a frequency of Q4W until the central macular retinal thickness (CST) meets a predetermined reference CST threshold; c) from this point onward, the dosing interval is extended, shortened, or maintained based on assessments made at the dosing visits, the assessments being based on the relative changes in CST and best corrected visual acuity (BCVA) compared to individual reference CST and BCVA; The minimum treatment interval that can be specified is Q4W, wherein i) the interval is extended by 4 weeks if: the CST value increases or decreases by ≤ 10% without an associated BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if either of the following criteria is met: the CST value decreases by > 10%; or the CST value decreases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters, or the CST value increases by > 10% and ≤ 20% without an associated BCVA decrease of ≥ 5 letters; iii) the interval is shortened by 4 weeks if either of the following criteria is met: the CST value increases by > 10% and ≤ 20% with an associated BCVA decrease of ≥ 5 to < 10 letters, or the CST value increases by > 20% without an associated BCVA decrease of ≥ 10 letters; or the CST value increases by ≤ 10% with an associated BCVA decrease of ≥ 10 letters; iv) The interval is shortened to Q4W under the following conditions: if the CST value increases by >10%, accompanied by a decrease in the associated BCVA of ≥10 letters, where, When the initial CST threshold criteria are met, the individual reference central macular retinal thickness (CST) is the CST value, and if the CST decreases by >10% relative to the previous reference CST at two consecutive drug visits, the reference CST is adjusted, and the obtained equivalent value is within 30 µm, such that the CST value obtained at a later visit will serve as the new reference CST; and the reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous drug visit.

2. As requested in item 1, wherein the dosing interval from week 24 onwards may be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

3. As claimed in claim 2, wherein the fluxipimab is administered at a concentration of approximately 120 mg / ml.

4. For any of the uses in claims 1 to 3, where the patient with ocular vascular disease has not previously been treated with anti-VEGF therapy.

5. For any of the uses described in claims 1 to 3, where the patient with ocular vascular disease has previously been treated with anti-VEGF therapy.

6. As requested in any of claims 1 to 3, wherein the fluoxetine is administered according to a determination made by a software tool.

7. A method for personalized dosing schedules based on personalized treatment intervals (PTIs) for patients with ocular vascular disease, wherein the ocular vascular disease is selected from macular edema secondary to central retinal vein occlusion, hemiretinal vein occlusion, or branch vein occlusion, the method comprising: receiving patient data in a computing system, the patient data including the patient's central macular retinal thickness (CST) and best corrected visual acuity (BCVA); using the computing system, based on the received patient data compared with individual reference CST and BCVA, extending, shortening, or maintaining the dosing interval, wherein the minimum treatment interval is Q4W; and obtaining a PTI based on the dosing interval, wherein i) the interval is extended by 4 weeks if: the CST value increases or decreases by ≤ 10% without a corresponding BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if either of the following criteria is met: the CST value decreases by > 10%; or the CST value decreases by ≤ 10% with a corresponding BCVA decrease of ≥ 10 letters. iii) The interval is shortened to 4 weeks if any of the following criteria are met: if the CST value increases by >10% and ≤20%, accompanied by a BCVA decrease of ≥5 to <10 letters; or if the CST value increases by >20%, accompanied by a BCVA decrease of ≥10 letters; or if the CST value increases by ≤10%, accompanied by a BCVA decrease of ≥10 letters; iv) The interval is shortened to Q4W if: the CST value increases by >10%, accompanied by a BCVA decrease of ≥10 letters; wherein when the initial CST threshold criteria are met, the individual reference CST is the CST value, and if the CST decreases by >10% relative to the previous reference CST of two consecutive dosing visits, the reference CST is adjusted, and the obtained equivalent value is within 30 weeks. Within µm, such that the CST value obtained at a subsequent visit will serve as the new reference CST; and wherein the reference BCVA is the average of the three best BCVA scores obtained at any previous medication visit.

8. The method of claim 7, further comprising: receiving updated patient information in the computing system; using the computing system to continuously update or maintain the dosing interval based on the updated patient information; and generating visualizations, user interfaces, or notifications based on the updated or maintained dosing interval.

9. Use of a personalized dosing schedule based on a personalized treatment interval (PTI) of 6 mg of fluxipimab for patients with macular edema secondary to central retinal vein occlusion, hemiretinal vein occlusion, or branch vein occlusion, wherein the calculation system obtains the PTI by: receiving patient data including the patient's central macular retinal thickness (CST) and best corrected visual acuity (BCVA); and extending, shortening, or maintaining the dosing interval based on the received patient data compared with individual reference CST and BCVA, wherein the minimum treatment interval is Q4W; wherein i) the interval is extended by 4 weeks if: the CST value increases or decreases by ≤ 10% without a corresponding BCVA decrease of ≥ 10 letters; or ii) the interval is maintained if either of the following criteria is met: the CST value decreases by > 10%; or if the CST value decreases by ≤ 10% with a corresponding BCVA decrease of ≥ 10 letters, or if the CST value increases by > iii) The interval is shortened to 4 weeks if any of the following criteria are met: 10% and ≤ 20% CST increase with a corresponding BCVA decrease of ≥ 5 to < 10 letters; or if the CST increase is > 20% without a corresponding BCVA decrease of ≥ 10 letters; or if the CST increase is ≤ 10% with a corresponding BCVA decrease of ≥ 10 letters; iv) The interval is shortened to Q4W if: the CST increase is > 10% with a corresponding BCVA decrease of ≥ 10 letters; wherein when the initial CST threshold criteria are met, the individual reference CST is the CST value, and if the CST decreases by > 10% relative to the previous reference CST at two consecutive dosing visits, the reference CST is adjusted, and the obtained equivalent is within 30 weeks. Within µm, such that the CST value obtained at a subsequent visit will serve as the new reference CST; and wherein the reference BCVA is the average of the three best BCVA scores obtained at any previous medication visit.

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