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Retinal Physician

Article

Bispecific Antibodies in Retina Therapies

More targets could mean better efficacy.

By: René Rückert, MD, MBA, Gemmy Cheung Chui Ming, FRCOphth, Marion R. Munk, MD, PhD, FEBO
Retinal Physician September 1, 2023 Vol 20, Issue September 2023 Page(s): 31-33

From the Archives

Bispecific antibodies are a type of therapeutic antibody that can simultaneously bind to 2 different targets, typically 2 distinct antigens. They can be designed to bridge 2 different molecules or cells together, bringing them into close proximity and allowing for specific interactions. They may also be designed to activate and/or block different cell surface receptors to modulate biologic responses to growth factors like vascular endothelial growth factor (VEGF) or block binding of cell-surface molecules like integrins. This unique characteristic of bispecific antibodies makes them a promising tool in the field of ophthalmic therapies and the treatment of retinal pathologies like age-related macular degeneration (AMD) or diabetic macular edema (DME). Traditional monoclonal antibodies typically have a Y-shaped structure, with 2 identical binding sites that recognize a single target antigen. In contrast, bispecific antibodies are engineered to possess 2 different binding domains, each with specificity for a different antigen. This enables bispecific antibodies to engage multiple targets simultaneously, leading to several potential superior therapeutic applications. Most bispecific antibodies in clinical development target tumors, including breast cancer, leukemia, lymphoma, and solid tumors, and in recent years, several bispecific antibodies have gained approval from regulatory agencies for the treatment of certain cancers. Furthermore, bispecific antibodies are also tested to treat hemophilia A, diabetes, pneumonia caused by bacteria, and Alzheimer disease. There are various formats and designs of bispecific antibodies, each with its own mechanism of action. Despite their promising potential, there are challenges associated with the development and manufacturing of bispecific antibodies, including complexity and stability. However, ongoing research and advancements in biotechnology are addressing these challenges, paving the way for wider application of bispecific antibodies. The specific challenges of bispecific antibodies during production have recently been summarized in an excellent review.1

The current gold-standard therapy for retinal pathologies like neovascular AMD (nAMD), DME, and retinal vein occlusion (RVO) involves blocking VEGF using single-targeted biologics (antibodies, antibody fragments, and a fusion protein). Blocking VEGF using aflibercept (Eylea; Regeneron), brolucizumab (Beovu; Novartis), ranibizumab (Lucentis; Genentech) or (off-label) bevacizumab (Avastin; Genentech) has demonstrated excellent safety and good efficacy in most patients, but a considerable high unmet medical need remains in treatment efficacy, duration, and long-term benefit. The approval of faricimab (Vabysmo; Roche/Genentech) marked the start of the routine clinical use of a bispecific antibody therapy in retinal disease. This paper will provide a short overview of the developing landscape of bispecific antibody therapy in retinal pathologies, based on published information to date.

APPROVED BISPECIFIC ANTIBODY THERAPY

Faricimab was approved in 2022 and is indicated for the treatment of nAMD and DME. It is under regulatory review for approval as a therapy for RVO. Faricimab is a humanized bispecific immunoglobulin G1 (IgG1) antibody that binds both VEGF-A and angiopoietin-2 (Ang2). The fragment crystallizable (Fc) region of faricimab was engineered by selected point mutations to abolish binding interactions with Fcg and FcRn receptors. Faricimab has a total molecular weight of approximately 149 kDa and is produced by recombinant DNA technology using mammalian Chinese hamster ovary (CHO) cell culture.

Targeting the Tie-2 pathway is hypothesized to lead to vascular stabilization. Clinical trials evaluating faricimab in nAMD and DME have shown similar efficacy as the current gold-standard, aflibercept with some advantage in the duration of the therapeutic effect after each injection. More data will be needed to demonstrate the benefit or any mechanistical superiority of blocking Ang2 in addition to VEGF alone — as stated on the manufacturer’s website, the benefit of blocking Ang2 has not been fully determined.

BISPECIFIC ANTIBODIES IN DEVELOPMENT

Several of the bispecific antibodies being developed for use in retinal pathologies target angiogenesis, with blockage of Ang2 (along with the well-established blocking of VEGF) being the most prominent target molecule and pathway. New pathways being investigated include blocking inflammation by targeting interleukin 6 (IL-6) (KSI-501; Kodiak Sciences), as well as blocking VEGF C, integrins, and complement.

AG-73305 (Allgenesis Biotherapeutics) is a first-in-class bispecific molecule that simultaneously binds to VEGF and integrins, with potential as a treatment for DME, nAMD, and other retinal diseases such as RVO. The drug is undergoing phase 2a study. It is a single fusion protein that simultaneously binds with high potency and specificity to VEGF and integrins, which are known to be involved in retinal diseases. Integrins have been shown to affect inflammation, fibrosis, and neurodegeneration, and have become important new targets for the potential treatment of retinal diseases. AG-73305 has the potential to treat anti-VEGF responders and nonresponders. This is a unique molecule that has demonstrated antiangiogenic, anti-inflammatory and antifibrotic activity in preclinical models.2

BI 836880 (Boehringer Ingelheim) is a humanized bispecific nanobody comprising 2 single variable domains that bind to all splice variants of VEGF (VEGF-165, VEGF-121, and VEGF-189) and Ang2, inhibiting binding of VEGFR-2 and Tie2. It also contains an additional albumin module that extends half-life in vivo.3 BI 836880 is being tested in clinical studies for treatment of nAMD and DME and has also been studied in oncology for the therapy of solid tumors.

IGT-427 (Ingenia Therapeutics and Mosaic Biosciences) is a bispecific antibody that simultaneously suppresses VEGF signaling and activates Tie2 signaling pathways in heterologous CHO cells and vascular endothelial cells.4 IGT-427 has potential to activate Tie2 signaling more strongly and durably over Ang2 inhibition. It is an early-stage asset, targeting primarily DME patients. The company is generating preclinical data to support transition to clinical studies.

ASKG-712 (AffaMed Therapeutics) is a bispecific molecule that targets VEGF and Ang-2 to address specific needs in ophthalmology, including nAMD and DME. The first patient in a phase 1 clinical trial of ASKG-712 for nAMD was dosed in June 2022.

IBI333 (Innovent Biologics) is a recombinant anti-VEGF-A and VEGF-C bispecific fusion protein. It consists of 3 parts: a peptide domain derived from VEGF receptor, a Fc functional region of human IgG1, and an anti-VEGF-C single-domain antibody. IBI333 can block the VEGF-A–mediated signaling pathway to inhibit vascular endothelial cell proliferation, thereby inhibiting angiogenesis and reducing vascular leakage. Meanwhile, IBI333 can also reduce the epithelial cell window formation induced by VEGF-C. This strategy with the bispecific blocking of VEGF-A and VEGF-C may further reduce vascular permeability and may inhibit the activity of compensatory upregulated VEGF-C, thereby achieving a more comprehensive and effective blocking of intraocular VEGF signaling. This compound is currently being studied in a phase 1 clinical study in patients with nAMD, according to the company.

KSI-501 is an investigational bispecific trap-antibody fusion biopolymer conjugate. It is designed to inhibit 2 mechanisms implicated in retinal diseases: VEGF and IL-6, a proinflammatory cytokine and growth factor. It is intended to provide potent inhibition of VEGF-mediated angiogenesis and vascular permeability through a soluble decoy receptor that inhibits the VEGF-A and placental growth factor (PLGF) binding to their cognate receptors. KSI-501 also offers IL-6-mediated inflammation inhibition through an antibody that binds soluble IL-6, inhibiting its binding to soluble as well as membrane-bound IL-6 receptors. This compound is currently in a phase 1 clinical study.5,6

KSI-601 (Kodiak Sciences) is a fusion protein developed by fusing an IL-1 receptor to an anti-HTRA1 antibody. HTRA1 (high-temperature requirement protein 1) is a serine protease and is involved in many different aspects of cell growth and also in epithelial to mesenchymal transition. HTRA+ is a genetic risk factor associated with geographic atrophy. KSI-601 is in preclinical development for the treatment of dry AMD.7,8

RO-101 (RevOpsis Therapeutics) targets both VEGF-A and Ang2 and is aimed to be developed for the treatment of nAMD, DME, and RVO targeting clinically validated pathways to address unmet needs in large, highly prevalent, and other serious sight-threatening ophthalmic diseases.9 Other drug candidates from RevOpsis, RO-102 and RO-104 for dry AMD and retinal vascular diseases, are in early discovery and yet not specified.10

APL-2006 (Apellis Pharmaceuticals) is a bispecific C3 and VEGF inhibitor designed for the treatment of nAMD. Apellis reported that it planned to submit an investigational new drug application in 2023.11

Although the list of new bispecific antibodies provided above may not be complete, it demonstrates that several companies are working to improve the efficacy of retinal therapies. It remains to be demonstrated, however, that more is better in the targeted approach to retinal pathologies.

CONCLUSION

Bispecific antibodies are a novel class of therapeutic antibodies that can bind to 2 different targets simultaneously. They may offer unique advantages in the field of retinal therapy, but more data will be needed in the future to learn more about potential benefits of approved or development-stage bispecific antibodies over the established single-target biologics used today in the clinic. RP

René Rückert, MD, MBA, is an immunologist who is board certified in biochemistry at Charité in Berlin, Germany. He is an independent consultant for ophthalmic drug and medical device development with Eyegnos Consulting. He reports that he is the founder of Eyegnos Consulting and a shareholder of Roche. Marion R. Munk, MD, PhD, FEBO, specializes in uveitis and medical retina and is head of research at Gutblick in Pfäffikon, Switzerland. She is adjunct faculty at Northwestern University, Chicago, and Chief Medical Officer of Isarna Therapeutics. She reports that she is the cofounder of Eyegnos Consulting, a shareholder of Roche, and a consultant for Roche, Bayer, Boehringer-Ingelheim, and Apellis. Gemmy Cheung Chui Ming, FRCOphth, is the Arthur Lim Professor in Ophthalmology at Duke-NUS, National University of Singapore. She reports consultancy to and grant funding from Roche and Boehringer Ingelheim. Reach Dr. Munk at marion_munk@hotmail.com.

REFERENCES

  1. Ma J, Mo Y, Tang M, et al. Bispecific antibodies: from research to clinical application. Front Immunol. 2021;12:626616. doi:10.3389/fimmu.2021.626616
  2. Cherukury M, Wu A, Chang B, Nguyen T, Wheeler LA. AG-73305, a novel multi-specific Fc-fusion protein for the treatment of diabetic macular edema. Invest Ophthalmol Vis Sci. 2019;60(9):3663.
  3. Le Tourneau C, Becker H, Claus R, et al. Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors. ESMO Open. 2022;7(5):100576. doi:10.1016/j.esmoop.2022.100576
  4. Furfine E, Slocum J, Capehart S, et al. Variants of IGT-427 are long-acting, bispecific antibodies for the treatment of degenerative retinal diseases. Invest Ophthalmol Vis Sci. 2022;63(7):678.
  5. Lin J, Correa F, Prasad N, et al. KSI-501 is a novel anti-VEGF and anti-IL-6 bispecific biopolymer conjugate to simultaneously address neovascularization and inflammation in retinal diseases. Invest Ophthalmol Vis Sci. 2023;64:1153.
  6. Kodiak Sciences. Kodiak Sciences announces upcoming presentations on its product and research pipeline at ARVO 2023 annual meeting. News release. Accessed August 2, 2023. https://ir.kodiak.com/news-releases/news-release-details/kodiak-sciences-announces-upcoming-presentations-its-product-and/
  7. Song K, Correa F, Shen Y, et al. Development of a modular IL-1 trap and anti-HTRA1 bispecific for the treatment of dry AMD. Invest Ophthalmol Vis Sci. 2023;64:1152.
  8. Kodiak Sciences. Our pipeline. Accessed August 2, 2023. https://kodiak.com/our-pipeline
  9. Patel P, Xu L, Paidela M, et al. Binding characteristics of the VEGF arm of a novel bispecific protein RO-101 in comparison to faricimab-svoa. Invest Ophthalmol Vis Sci. 2023;64:738.
  10. RevOpsis. Our platform. Accessed August 2, 2023. https://revopsis.com/our-platform/
  11. Apellis Pharmaceuticals reports fourth quarter and full year 2022 financial results. News release. Accessed August 2, 2023. https://investors.apellis.com/news-releases/news-release-details/apellis-pharmaceuticals-reports-fourth-quarter-and-full-year-4

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