Depatuxizumab Mafodotin (ABT-414) Drug Description

Depatuxizumab Mafodotin, also konwn as ABT-414 is an investigational anti-EGFR (epidermal growth factor receptor) monoclonal (mAb) antibody drug conjugate or ADC. [1][2] As an ADC, Depatuxizumab Mafodotin (ABT-414) is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells.

Researchers at Abbvie are developing the drug with components in-licensed from Life Science Pharmaceuticals, and Seattle Genetics.

AbbVie is evaluating it for the treatment of adult patients with EGFR-amplified glioblastoma, an aggressive malignant primary brain tumor.[3][4] In 2014, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency granted Orphan Drug Designation for the treatment of adult glioblastoma and glioma, respectively. [5][6] In 2016, the FDA granted Rare Disease Designation to Depatuxizumab Mafodotin (ABT-414) for the treatment of pediatric patients with EGFR-amplified Diffuse Intrinsic Pontine Gliomas (DIPG). ABT-414 is an investigational compound

Mechanism of Action
ABT-414 targets cancer cells by linking the anti-microtubule agent monomethyl auristatin F (MMAF) with an antibody directed against the epidermal growth factor receptor (EGFR) or mutant EGFRvIII.
[7] This combination in a single drug is called an antibody-drug conjugate or ADC.

As an antibody-drug conjugate, Depatuxizumab Mafodotin (ABT-414) is designed to be stable in the bloodstream and to release the potent chemotherapy agent only inside targeted cancer cells. Studies are being conducted to determine if this approach can reduce the toxic side effects of traditional chemotherapy while enhancing anti-tumor activity.[8]

Clinical trial
Depatuxizumab Mafodotin (ABT-414) is currently being investigated in Phase I/II trials for the treatment of glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor. ABT-414 is also in clinical trials for the treatment of patients with squamous cell tumors, including non-small cell lung cancer. The trial drug is an investigational compound and its efficacy and safety have not been established by the FDA or any other health authority.

A retrospective, observational clinical study designed to review the corneal toxicity or CT in glioblastoma patients, investigators observed that Depatuxizumab Mafodotin (ABT-414) demonstrated very promising preliminary results.

However, all participating patients developed corneal toxicity which resulting in debilitating ocular symptoms. The observed symptoms included eye pain, photophobia, red eyes and decreased vision and varied in severity between patients.

Of the 12 participating patients, 4 needed to discontinue treatment, while others required a decrease in the dosing of Depatuxizumab Mafodotin (ABT-414).  In these patients corneal toxicity presented with intra-epithelial corneal cysts, filamentary keratitis, corneal abrasions, whorl keratopathy, stromal opacities, and punctate epithelial erosions, all resembling advanced limbal stem cell dysfunction.  These patients were treated with topical dexamethasone as part of the Depatuxizumab Mafodotin (ABT-414) Trial, however, the investigators noted that prednisolone acetate 1% was more effective in stabilizing and reversing the corneal toxicities.

Further studies into the relationship between EGFR in the cornea and the mechanism of action of Depatuxizumab Mafodotin (ABT-414) and a protocol for the treatment or prevention of the corneal toxicity are required for this and other related antibody-drug conjugate treatments for GBM.