Characterization and Potential Mitigation of Corneal Effects in Nonclinical Toxicology Studies in Animals Administered Depatuxizumab Mafodotin

Loberg, Lise I.; Henriques, Tracy; Johnson, Julie K.; Miller, Paul E.; Ralston, Sherry L.

doi:10.1089/jop.2022.0006

Cited by 3 publications

(1 citation statement)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, there were no significant microscopic findings in the eye. Emphasis was placed on evaluating cornea as corneal toxicity has been reported after intravenous administration of ABT-414 in previous nonclinical studies [ 24 ] and clinical trials [ 13 ] ( Figure 5 a).…”

Section: Resultsmentioning

confidence: 99%

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

et al. 2022

View full text Add to dashboard Cite

Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.

show abstract

Section: Resultsmentioning

confidence: 99%

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

et al. 2022

View full text Add to dashboard Cite

show abstract

Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody–Drug Conjugates (ADCs)

Lindgren,

Yan,

Cil

et al. 2024

Curr Ophthalmol Rep

View full text Add to dashboard Cite

Purpose of Review This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody–drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs). Recent Findings ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity. Summary Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

show abstract

Antibody-Drug Conjugates and Ocular Toxicity

Jaffry,

Choudhry,

Aftab

et al. 2023

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Characterization and Potential Mitigation of Corneal Effects in Nonclinical Toxicology Studies in Animals Administered Depatuxizumab Mafodotin

Cited by 3 publications

References 14 publications

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody–Drug Conjugates (ADCs)

Antibody-Drug Conjugates and Ocular Toxicity

Contact Info

Product

Resources

About