Generation and characterization of ABBV642, a dual variable domain immunoglobulin molecule (DVD-Ig) that potently neutralizes VEGF and PDGF-BB and is designed for the treatment of exudative age-related macular degeneration

Ding, Kun; Eaton, Lucia J.; Bowley, Diana R.; Rieser, Matthew J.; Chang, Qing; Harris, Maria C.; Clabbers, Anca; Feng, Daxiong; Shen, Jikui; Hackett, Sean F.; Touw, Debra S.; Bixby, Jacqueline G.; Zhong, Suju; Benatuil, Lorenzo; Bose, Sahana; Grinnell, Christine; Preston, Gregory M.; Iyer, Ramesh; Sadhukhan, Ramkrishna; Marchie, Susan; Overmeyer, Gary; Ghayur, Tariq; Riet, Deborah A. van; Tang, Shibo; Campochario, Peter A.; Gu, Jijie

doi:10.1080/19420862.2016.1268305

Cited by 22 publications

(15 citation statements)

References 37 publications

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“…Next, the half-life of 441 in mice was determined, and found to be 45 h (Supplementary Fig. 5b ) and thus comparable to a closely related format, the DVD-IgG, for which the half-life in mice was also reported to be about 67 h 49 .…”

Section: Resultsmentioning

confidence: 73%

Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

et al. 2021

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The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model.

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Section: Resultsmentioning

confidence: 73%

Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

et al. 2021

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“…Some of these issues evolve from the use of mono-factor therapies, such as anti-VEGF drugs, to address a multifactorial, multi-genetic disease, as is the case of nAMD. In order to improve effectiveness, combination of treatment with other proangiogenic inhibitors as blocking PDGF ( [183,184], clinicaltrials.gov/NCT01940900), steroids, e.g., triamcinolone [185], or AINEs, such as ketorolac [186], and integrin antagonists [187] has been suggested as adjuvants to anti-VEGF regiments. Collectively, these novel therapeutic approaches indicate the need to simultaneously address a multitude of nAMD-associated factors.…”

Section: Addressing Unmet Needs In Namd Treatmentmentioning

confidence: 99%

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

Mammadzada

Corredoira

André

2019

Cell. Mol. Life Sci.

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Understanding the mechanisms that underlie age-related macular degeneration (AMD) has led to the identification of key molecules. Hypoxia-inducible transcription factors (HIFs) have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of nAMD. This knowledge has propelled the development of a new group of therapeutic strategies focused on gene therapy. The present review provides an update on current gene therapies in ocular angiogenesis, particularly nAMD, from both basic and clinical perspectives.

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“…The main pathological change in exudative AMD is the formation of choroidal neovascularization (CNV) in the macular region (1,3,7). Many studies have shown that overexpression of vascular endothelial growth factor (VEGF) plays a decisive role in its pathogenesis (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Factors for Visual Acuity Improvement After Anti-VEGF Treatment of Wet Age-Related Macular Degeneration in China: 12 Months Follow up

Huang

Zhang

et al. 2021

Front. Med.

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Purpose: To evaluate the treatment solutions and effectiveness of intravitreal ranibizumab (RBZ) or conbercept in patients with wet age-related macular degeneration (wAMD) in a real-life setting in China.Methods: The medical records of 368 patients with wAMD who started RBZ or conbercept treatment between 1 May 2014 and 30 April 2018 were evaluated. All patients were defined on fundus angiography at baseline to determine the subtype of AMD (PCV or CNV). We report visual acuity (VA) and central retinal thickness (CRT) measurements at baseline and 12 months.Results: The average number of anti-VEGF injections was 2.1 ± 1.2. The BCVA improvement of these two groups was similar with a difference of 1.00 letter (95% CI: −1.4~3.4, p = 0.8505). At the end of the study, a BCVA increase of at least 5 letters was determined to be a satisfactory efficacy endpoint. Several factors were related to the possible improvement in the satisfactory efficacy endpoint, including female sex (OR 2.07, 95% CI 1.22~3.51), number of injections (OR 1.40, 95% CI 1.12~1.75) and VA change at the first month (OR 13.75, 95% CI 7.41~25.51). Additionally, some factors were related to the possible reduction in the satisfactory efficacy endpoint, including diabetes (OR 0.27, 95% CI 0.10~0.73) and disease history (OR 0.75, 95% CI 0.57~0.98).Conclusion: Our study demonstrates that anti-VEGF drugs can effectively improve BCVA and reduce CRT in AMD patients. Sex, number of injections, VA change at the first month, diabetes and disease history are the most important factors affecting visual acuity.

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Generation and characterization of ABBV642, a dual variable domain immunoglobulin molecule (DVD-Ig) that potently neutralizes VEGF and PDGF-BB and is designed for the treatment of exudative age-related macular degeneration

Abstract: Exudative age-related macular degeneration (AMD) is the most common cause of moderate and severe vision loss in developed countries.

Cited by 22 publications

References 37 publications

Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

Factors for Visual Acuity Improvement After Anti-VEGF Treatment of Wet Age-Related Macular Degeneration in China: 12 Months Follow up

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