Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy

Tom, Irene; Pham, Victoria C.; Katschke, Kenneth J.; Li, Wei; Liang, Wei-Ching; Gutierrez, Johnny; Young, Andrew Ah; Figueroa, Isabel; Eshghi, Shadi Toghi; Lee, Chingwei V.; Kanodia, Jitendra; Snipas, Scott J.; Salvesen, Guy S.; Lai, Phillip; Honigberg, Lee; Campagne, Menno van Lookeren; Kirchhofer, Daniel; Baruch, Amos; Lill, Jennie R.

doi:10.1073/pnas.1917608117

Cited by 39 publications

(54 citation statements)

References 39 publications

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“…10 HTRA1 is a secreted serine protease expressed by a number of tissues 10,12 and cleaves a large number of substrates. Its substrates include extracellular matrix proteins that are potentially involved in retinal degeneration, such as epithelial growth factor-containing fibulin-like extracellular matrix protein 1 and clusterin, 13,14 as well as retinol-binding protein 3, a key protein in the visual cycle. 14 In addition, transgenic mice overexpressing HtrA1 in retinal pigment epithelial (RPE) recapitulated cardinal features associated with advanced AMD and polypoidal choroidal vasculopathy, including branching networks of choroidal vessels and severe degeneration of the elastic laminae.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

Khanani

Hershberger²,

Pieramici

et al. 2021

American Journal of Ophthalmology

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Section: Introductionmentioning

confidence: 99%

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

Khanani

Hershberger²,

Pieramici

et al. 2021

American Journal of Ophthalmology

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“…Furthermore, in vivo pharmacologic inhibition of HTRA1 enzymatic activity was observed following ITV injection of FHTR2163 into cynomolgus monkey eyes. 30 These data support the cynomolgus monkey as the only appropriate species due to physical anatomy of the eye, expression of the target epitope, functional engagement by FHTR2163, and favorable pharmacokinetic (PK) characteristics with respect to drug exposure and immunogenicity.…”

Section: Methodsmentioning

confidence: 62%

Nonclinical Safety Assessment of FHTR2163, An Antigen-Binding Fragment Against HTRA1 for the Treatment of Geographic Atrophy

Dere¹,

Crowell²,

Maia³

et al. 2020

Toxicol Pathol

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FHTR2163 is an antigen-binding fragment of a humanized immunoglobulin G1 monoclonal antibody directed against high-temperature requirement A serine peptidase 1 (HTRA1) that is being developed as a potential intravitreal (ITV) treatment for patients with geographic atrophy (GA), an advanced form of dry age-related macular degeneration. The nonclinical toxicology program was designed to assess the safety and tolerability of HTRA1 inhibition following ITV administration of FHTR2163 to support ITV administration in patients with GA. FHTR2163 was well tolerated in a single-dose ITV-administered 8-day toxicity study in cynomolgus monkeys following a 50 µL high (>700 mOsm/kg) osmolality formulation up to 12.5 mg/eye; however, 100 µL (2× 50 µL injections) of a high-osmolality formulation resulted in transient retinal detachment. Repeat-dose ITV administration every 2 weeks of FHTR2163 was well tolerated in 8- and 26-week studies with ITV injection of 100 µL (2× 50 μL) of iso-osmolar formulation up to 15 mg/eye, or 50 µL of the high-osmolality formulation up to 12.5 mg/eye. Observed transient and reversible ocular effects included inflammation and perivascular infiltrates, consistent with an immune response attributed to the administration of heterologous (humanized) protein. Overall, FHTR2163 was well tolerated, and the nonclinical package supported the continued clinical development of FHTR2163 in patients with GA.

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“…Possibly, these include genetic variations, inflammatory status and/or other characteristics not encountered for in this study. Recent evidence indicates that the extracellular matrix serine protease, HtrA1, can target DKK3 for degradation and may regulate its levels, at least in aqueous humor of the eye 26 . The role of HtrA1 in controlling plasma DKK3 protein levels is unknown, but deserves attention in future investigations.…”

Section: Discussionmentioning

confidence: 99%

The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population

Piek

Smit

Suthahar

et al. 2021

Sci Rep

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Dickkopf-3 (DKK3) is an emerging biomarker for cardiovascular disease (CVD) and chronic kidney disease (CKD). Herein, baseline DKK3 plasma levels were measured in 8420 subjects from the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort, a large general population cohort, using enzyme-linked immunosorbent assays. Associations with clinical variables and outcomes were analysed. Median DKK3 level was 32.8 ng/ml (28.0–39.0). In multivariable linear regression analysis, the strongest correlates for plasma DKK3 were age, body mass index and estimated glomerular filtration rate (eGFR). At baseline, 564 (6.7%) subjects had CVD (defined as a myocardial infarction and/or cerebrovascular accident) and 1361 (16.2%) subjects had CKD (defined as eGFR < 60 ml/min/1.73m2 and/or urinary albumin excretion (UAE) > 30 mg/24 h). Of subjects with known CVD and CKD follow-up status (respectively 7828 and 5548), 669 (8.5%) developed CVD and 951 (17.1%) developed CKD (median follow-up respectively 12.5 and 10.2 years). Crude logistic regression analysis revealed that DKK3 levels were associated with prevalent CVD (Odds ratio: 2.14 [1.76–2.61] per DKK3 doubling, P < 0.001) and CKD (Odds ratio: 1.84 [1.59–2.13] per DKK3 doubling, P < 0.001). In crude Cox proportional hazard regression analysis, higher DKK3 levels were associated with higher risk for new-onset CVD (Hazard ratio: 1.47 [1.13–1.91] per DKK3 doubling, P = 0.004) and CKD (Hazard ratio: 1.45, [1.25–1.69] per DKK3 doubling, P < 0.001). However, these associations remained no longer significant after correction for common clinical variables and risk factors, though independently predicted for new-onset CKD in a subgroup of subjects with the lowest UAE values. Together, DKK3 plasma levels are associated with cardiovascular risk factors, but are generally not independently associated with prevalent and new-onset CVD and CKD and only predicted for new-onset CKD in those subjects with the lowest UAE values.

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Development of a therapeutic anti-HtrA1 antibody and the identification of DKK3 as a pharmacodynamic biomarker in geographic atrophy

Cited by 39 publications

References 39 publications

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

Nonclinical Safety Assessment of FHTR2163, An Antigen-Binding Fragment Against HTRA1 for the Treatment of Geographic Atrophy

The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population

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