New Monoclonal Antibody Treatments in Retina

An alphabet soup with potential to preserve vision.

There is no question that the introduction of monoclonal antibodies has changed the field of medicine. In the field of retina, specifically, several blockbuster anti-VEGF drugs have demonstrated unparalleled effectiveness in the treatment of multiple retinal diseases. The question now becomes, what is on the horizon for new monoclonal antibody-based treatments in retinal disease?

Amy S. Babiuch, MD is from the Cleveland Clinic in Cleveland, Ohio. Dr. Babiuch reports personal fees from MCME Global and Allergan. She can be reached at


Around the turn of the 20th century, Emil von Behring and Paul Ehrlich pioneered the applications of antibodies through their work in serum therapy in medicine. Since that time, immense progress has been made and multiple therapeutic antibodies exist for treatment of a number of debilitating systemic diseases, including certain cancers and inflammatory diseases. In the eye, monoclonal antibodies are used to manage diseases including but not limited to uveitis, neovascular AMD, choroidal neovascularization (CNV), retinal neovascularization, and macular edema secondary to diabetes and retinal vein occlusions.

The most common monoclonal antibody-based therapeutics are humanized and fully human antibodies. Humanized antibodies, like ranibizumab (Lucentis; Genentech) and bevacizumab (Avastin; Genentech), replace only the antigen binding site from the human antibody with that of the specific mouse region.1 The preparation of fully human antibodies, like adalimumab (Humira; AbbVie, Inc.), is via transgenic mice and phage display technology.2 Currently, antibodies are produced as monospecific, human, or nearly human molecules. They are modified to produce high-affinity target binding and serum half-life using affinity maturation, Fc engineering, and manipulation of glycoforms.3


Table 1 illustrates monoclonal antibody therapies used in the treatment of retinal disease and their phase of development.

Table 1: Targeted Disease Process, Mechanism of Action, Manufacturer, and Phase of Development of New Monoclonal Antibody-Based Treatments
GSK933776 GA in AMD Humanized monoclonal antibody against amyloid-beta GlaxoSmithKline Phase 2 completed: Drug is safe but did not slow GA growth.
Lampalizumab GA in AMD Antigen-binding fragment of a humanized monoclonal antibody Roche Phase 3 trials under way.
THR-317 DME Anti-PlGF recombinant monoclonal antibody Thrombogenics Phase 2 study under way.
RO6867461 (RG7716) DME, nvAMD Bispecific antibody blocking simultaneous Ang-2 and VEGF-A Hoffman LaRoche Phase 2 studies under way.
REGN910 (nesvacumab) DME, nvAMD Fully human IgG1 monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang-2 with high affinity, but shows no binding to Ang-1 Regeneron Pharmaceuticals Phase 2 studies under way.
DS7080a nvAMD Monoclonal antibody Daiichi Sankyo, Inc. Phase 1 study under way.
TK001 (sevacizumab) nvAMD Recombinant humanized monoclonal antibody Jiangsu T-Mab Biopharma Co., Ltd. Phase 1 study under way.
Brolucizumab (formerly RTH-258 & ESBA1008) nvAMD Humanized, single-chain antibody fragment that is much smaller than commercially available anti-VEGF agents Alcon Phase 2 studies completed, phase 3 under way.
REGN2176-3 nvAMD Combination antibody to PDGFR-b coformulated with aflibercept Regeneron Pharmaceuticals Phase 2 study terminated: no additional efficacy seen with REGN2176-3 over aflibercept alone.
iSONEP (LT1009) nvAMD Humanized monoclonal antibody against S1P (systemic administration) Lpath, Inc. Phase 2a completed: did not meet primary endpoints.
GA, geographic atrophy; AMD, age-related macular degeneration; DME, diabetic macular edema; PlGF, placental growth factor; nvAMD, neovascular age-related macular degeneration; Ang-2, angiopoeitin-2; VEGF, vascular endothelial growth factor; Ang-1, angiopoeitin-1; PDGFR, placental derived growth factor receptor; S1P, sphingosine-1-phosophate.

Dry Age-Related Macular Degeneration

Currently, retinal therapy centers around the neovascular form of AMD. But the more common form is dry AMD. Dry AMD can lead to debilitating vision loss due to geographic atrophy (GA), which progresses over time, first encircling the fovea, and then involving the fovea late in the course of disease. Prevalence is estimated at 0.70% at age 70 in populations of European ancestry, and it rises with age to 2.91% at age 80 and 11.29% at age 90.4 Forty percent to 50% of eyes with GA and good VA at baseline will lose 3 or more lines of vision by 2 years, and 27% will have 20/200 VA or worse in 4 years.5 Monoclonal antibody-based treatments targeting GA growth may lead to a potential vision-preserving benefit in this form of AMD.

GSK933776 (GlaxoSmithKline)

GSK933776 is a humanized mouse immunoglobulin G subclass 1 (IgG1) monoclonal antibody against amyloid-beta, which is delivered intravenously. Phase 1 and 2 studies have been completed in patients with advanced dry AMD. The phase 2 study revealed that monthly treatment was safe and well tolerated, but the drug failed to demonstrate slowing in the rate of GA enlargement. Currently, there are no plans to further investigate this drug for late-stage AMD.6

Lampalizumab (Roche)

Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD). Complement factor D is the rate-limiting enzyme in the activation of the alternative complement pathway. It has been implicated in the pathogenesis of AMD. Mouse models have shown that blocking activation of the alternative complement pathway is neuroprotective against light-induced photoreceptor degeneration, suggesting a relationship between the complement system and oxidative stress-mediated photoreceptor degeneration.7 Thus, inhibition of the alternative complement pathway may lead to slowed GA growth and preservation of VA.

MAHALO, the phase 2 study of the drug, enrolled 129 patients with bilateral GA without CNV, and it demonstrated a 20.4% reduction in GA lesion progression in patients treated with monthly intravitreal injections, as compared to sham at 18 months. Further, results in a subpopulation of patients positive for the complement factor I (CFI) biomarker demonstrated a 44% reduction in progression at 18 months.8

Based on these encouraging results, 2 phase 3 trials, CHROMA and SPECTRI, were initiated. These identically designed, double-masked, randomized studies will compare a 10-mg dose administered every 4 weeks or 6 weeks to sham injection. The primary objective is to demonstrate a reduction in the rate of GA disease progression at 1 year (48 weeks). Approximately 936 patients will be enrolled in each study, and the CFI biomarker will be further evaluated by enrolling biomarker-positive and biomarker-negative patients in each of the sham, 4-week, and 6-week arms.

Diabetic Macular Edema

Diabetic retinopathy and DME are common microvascular complications in patients with diabetes. Diabetic macular edema can develop at any stage of DR, but it occurs more frequently with increased duration and severity of disease. It is estimated that 14% of patients with diabetes have DME.9 In the past few years, the use of anti-VEGF and long-acting steroid-delivery implants have improved retina specialists’ ability to treat DME. Several monoclonal antibody treatments aimed at DME management are in the pipeline.

THR-317 (Thrombogenics)

THR-317 is an anti-placental growth factor (PlGF) recombinant monoclonal antibody. Placental growth factor is a VEGF homolog that regulates the angiogenic switch in disease, but not in health.10 THR-317 is in active phase 2 study outside the United States. The study will evaluate the safety of 3 intravitreal injections of 2 dose levels (4 mg or 8 mg) of THR-317 and will assess its ability to improve BCVA and to reduce central retinal thickness in subjects with DME.

RO6867461 (RG7716; Hoffman LaRoche)

RO6867461 is a bispecific humanized IgG1 monoclonal antibody that blocks simultaneous angiopoietin-2 (Ang2) and VEGF-A. An animal model of diabetes has shown that Ang2 is upregulated in the retina and causes increased vascular permeability. Further, VEGF and Ang2 act in concert to regulate vasculature and endothelial cell permeability in vitro.11

Currently the drug is undergoing 3 concurrent trials: 2 for neovascular AMD and one for DME. BOULEVARD is a phase 2, multiple-dose, randomized, active comparator-controlled, double-masked, parallel-group study to investigate efficacy in treatment-naive center-involving DME.

REGN910 (nesvacumab; Regeneron)

REGN910 is a fully human IgG1 monoclonal antibody that specifically binds Ang2 with high affinity but shows no binding to angiopoietin-1 (Ang1).12 Ang1 and Ang2 are ligands for the vascular endothelial cell receptor tyrosine kinase Tie2, and are proangiogenic factors expressed in angiogeneisis.13-16

Two concurrent trials, one for nvAMD and one for DME, are active. RUBY is an active-controlled, phase 2 study of the efficacy, safety, and tolerability of repeated intravitreal doses of this drug in patients with DME. The primary objective is to compare the efficacy of REGN910 to aflibercept in improving BCVA in patients with DME.

Neovascular Age-Related Macular Degeneration

Age-related macular degeneration is the leading cause of blindness in elderly individuals in high-income countries.4 Anti-VEGF monotherapy has become the mainstay of treatment in individuals who develop neovascular AMD. The development of further monoclonal antibodies, some of which are biosimilar, has the potential to offer additional therapies for clinical use.

DS7080a (Daiichi Sankyo, Inc.)

DS7080a is a monoclonal antibody proposed as a new treatment for neovascular AMD. It is currently in a phase 1 dose escalation and expansion trial. It has shown preliminary efficacy in patients with nvAMD either alone or in combination with ranibizumab.

TK001 (sevacizumab; Jiangsu T-Mab Biopharma Co., Ltd.)

TK001 is a recombinant humanized anti-VEGF monoclonal antibody. It is currently in an active phase 1 trial outside the United States evaluating safety, pharmacokinetics, and tolerability to determine the maximum tolerated dose in neovascular AMD subjects.

Brolucizumab (Alcon; formerly RTH-258 and ESBA-1008)

Brolucizumab is a humanized single-chain antibody fragment inhibitor of all VEGF-A isoforms, and it is much smaller than the commercially available anti-VEGF agents. Its smaller size allows for a higher molar dose per volume and potentially better ocular tissue penetration. The molecular weight is 26 kDa compared to 115 kDa and 48 kDa for aflibercept and ranibizumab, respectively.17 Additionally, compared to bevacizumab and ranibizumab, animal studies reveal a 4-fold lower systemic exposure.18

Brolucizumab has demonstrated noninferiority compared with ranibizumab in a phase 1/2 study.19 Further, the OSPREY study of 89 patients revealed noninferiority to aflibercept. These promising results sparked the initiation of 2 global phase 3 studies (HAWK and HARRIER).20

The OWL study is a phase 2 study evaluating the efficacy of microvolume injections or infusions of brolucizumab vs traditionally delivered monthly intravitreal ranibizumab injections. Microvolume infusions of brolucizumab occurred over a 16-minute period in the clinical office setting via an external pump connected to a cannula placed in the patient’s eye.21,22 A primary efficacy signal was detected in the study, and further, no safety issues preventing brolucizumab for microvolume delivery were noted.23

RO6867461 (RG7716; Hoffman LaRoche)

Two studies are under way to evaluate RO6867461 for AMD. AVENUE is a phase 2 study investigating the safety, tolerability, pharmacokinetics, and efficacy of RO6867461 in participants with CNV secondary to AMD. STAIRWAY is a phase 2 study to evaluate for extended durability in the treatment of neovascular AMD.

REGN910 (nesvacumab; Regeneron)

Concurrent trials, one for nvAMD and one for DME, are active. ONYX is a phase 2 study of efficacy, safety, and tolerability of repeated intravitreal doses of the drug. The primary objective is to compare efficacy of REGN910 to intravitreal aflibercept. The 3 arms include 2 REGN910 dosing regimens and 1 aflibercept arm.

A Note About Biosimilars

A biosimilar drug is a biological product that is highly similar, but not identical, to an already FDA-approved biological product (the reference product). A biosimilar has demonstrated no clinically meaningful differences from the reference product and has the same mechanism of action, route of administration, dosage form, and strength as the reference drug.24 The patent on Lucentis expires in the United States in 2020 and in Europe in 2022. Table 2 lists biosimilars in development.

Table 2: Reference Product, Manufacturer, and Phase of Development of Biosimilar Drugs
PF582 ranibizumab Pfenex, Inc. Pilot phase 1/2 completed.
FYB201 ranibizumab Bioeq GmbH, Formycon Recruiting for phase 3 (COLUMBUS-AMD) study.
CHS-3551 ranibizumab Coherus In pipeline.
Xlucane ranibizumab Xbrane Biopharma Company reports good results in a comprehensive in vitro biosimilarity study.
BCD-021 bevacizumab Biocad Clinical trials withdrawn due to poor enrollment.


In January 2017, Lucentis 0.5 mg was approved for the treatment of myopic CNV. This is the fifth FDA-approved indication for Lucentis since its initial release in 2006. Additionally, the LADDER trial, a phase 2 multicenter, randomized active treatment trial is enrolling patients for the ranibizumab port delivery system for sustained delivery of ranibizumab in patients with neovascular AMD. The implant is an intraocular refillable device that is surgically placed through the pars plana to allow for sustained delivery of ranibizumab into the vitreous. The results of the phase 3 VISUAL-I and VISUAL-II studies led to the approval of Humira for use in management of noninfectious intermediate, posterior, and panuveitis.25,26 This marks the 10th indication for Humira, and increases the relatively limited armamentarium for uveitis treatment.


Monoclonal antibody-based treatments have had a profound effect on the landscape of therapeutics in medicine, from improved quality of life, to life-preserving effects, to vision preserving effects. The new monoclonal antibody-based treatments listed here could just be the “next big thing.” RP


  1. Queen C, Schneider WP, Selick HE, et al. A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci U S A. 1989;86(24):10029-10033.
  2. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9(10):767-774.
  3. Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95(Pt B):158-172.
  4. Rudnicka AR, Jarrar Z, Wormald R, Cook DG, Fletcher A, Owen CG. Age and gender variations in armd prevalence in populations of european ancestry: a meta-analysis. Ophthalmology. 2012;119(3):571-580.
  5. Sunness JS. The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration. Mol Vis. 1999;5:25.
  6. Rosenfeld, PJ. Results of a Phase 2 Study using an Anti-Amyloid Beta Monoclonal Antibody for the Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration, Presented at: Retina Subspecialty Day, Chicago, IL; October 14, 2016.
  7. Rohrer B, Guo Y, Kunchithapautham K, Gilkeson GS. Eliminating complement factor D reduces photoreceptor susceptibility to light-induced damage. Invest Ophthalmol Vis Sci. 2007;48(11):5282-5289.
  8. Holz FG. The MAHALO phase II study: safety tolerability and evidence of activity of lampalizumab (anti-factor D) in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD), Presented at: Euretina; Hamburg, Germany; September 27, 2013.
  9. Girach A, Lund-Andersen H. Diabetic macular oedema: a clinical overview. Int J Clin Pract. 2007;61(1):88-97.
  10. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463-475.
  11. Rangasamy S, Srinivasan R, Maestas J, McGuire PG, Das A. A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011;52(6):3784-3791.
  12. Papadopoulos KP, Kelley RK, Tolcher AW, et al. A phase I first-in-human study of nesvacumab (REGN910), a fully human anti-angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2016;15;22(6):1348-1355.
  13. Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87(7):1161-1169.
  14. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55-60.
  15. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165-177.
  16. Thurston G, Daly C. The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. Cold Spring Harb Perspect Med. 2012;2(9):a006650.
  17. Tietz J, Spohn, G, Schmid G, et al. Affinity and potency of RTH258 (ESBA1008), a novel inhibitor of vascular endothelial growth factor a for the treatment of retinal disorders. Invest Ophthalmol Vis Sci. 2015;56(7):1501.
  18. Gaudreault J, Gunde T, Floyd HS, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53:3025.
  19. Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration. Ophthalmology. 2016;123(5):1080-1089.
  20. Singerman LJ, Weichselberger A, Sallstig P. OSPREY trial: randomized, active-controlled, phase II study to evaluate safety and efficacy of RTH258, a humanized single-chain anti-VEGF antibody fragment, in patients with neovascular AMD. Presented at: Association for Research in Vision and Ophthalmology Annual Meeting; Denver, CO; May 3-7, 2015.
  21. Berger BB, Yanni SE, Wenzel A, Weichselberger, Hubschman JP. Efficacy of RTH258 (ESBA1008), an anti-VEGF agent, applied by microvolume injection or infusion in subjects with neovascular AMD. Invest Ophthalmol Vis Sci. 2015;56(7):821.
  22. Arnold J, Weichselberger A, Weissgerber G, Schmidt W. RTH258, a novel single-chain anti-vascular endothelial growth factor (VEGF) antibody fragment, in patients with neovascular age-related macular degeneration (NAMD): results from phase II studies. Paper presented at: Annual Royal Australian and New Zealand College of Ophthalmologists Scientific Congress 2015; Wellington, New Zealand; October 31-November 4, 2015.
  23. Berger BB, Weichselberger A, Schmidt W. Microvolume drug delivery: a novel therapeutic strategy for patients with neovascular age-related macular degeneration (nAMD). Paper presented at: Retina Society Annual Meeting; Paris, France; October 7-11, 2015.
  24. U.S. Food and Drug Administration. Information for consumers (biosimilars). Available at: . Accessed May 9, 2017.
  25. Jaffe GJ, Dick AD, Br├ęzin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375(10):932-943.
  26. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183-1192.