Abstract
Preclinical development of ATR04-484, an auxotrophic strain of Staphylococcus epidermidis, for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity.
Author
person
Travis M. Whitfill
Azitra Inc., Branford, CT
info_outline
Travis M. Whitfill, Sara Mootien, Roger Leger
Full text
Authors
person
Travis M. Whitfill
Azitra Inc., Branford, CT
info_outline
Travis M. Whitfill, Sara Mootien, Roger Leger
Organizations
Azitra Inc., Branford, CT, Azitra inc., Branford, CT
Abstract Disclosures
Research Funding
No funding sources reported
Background:
Agents targeting the EGFR-mediated signaling pathway are commonly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers. Significant dermal toxicities, which occur in up to 90% of patients treated with EGFR inhibitors (EGFRis) and other therapies inhibiting downstream signaling pathways, may be disruptive to a patient’s quality of life and adherence to therapy. Inhibition of the EGFR pathway may suppress host defenses and lead to opportunistic pathogenic colonization or infection. EGFRi-induced dermal toxicity is associated with elevated levels of Staphylococcus aureus and IL-36γ. ATR04-484 is a topical ointment containing
S. epidermidis
strain SE484, isolated from a healthy human volunteer that was selected for its ability to inhibit
S. aureus
and IL-36γ
.
Methods:
Reconstructed human epidermis (RHE) and
ex vivo
pig skin were used to measure the effect of ATR04-484 on
S. aureus
in therapeutic and prophylactic settings with
S. aureus
added prior to or after ATR04-484, respectively. To evaluate the anti-inflammatory effects of ATR04-484, IL-36γ levels were measured on untreated RHE and RHE treated with erlotinib alone or in combination with ATR04-484. 10
4
colony-forming units (CFU) of methicillin-resistant (MRSA) or methicillin-sensitive (MSSA)
S. aureus
were used. Toxicology was assessed by measuring cell viability in three
in vitro
toxicology assays: the eye irritant potential was tested on 3D reconstituted human cornea-like epithelium (RhCE), the skin irritant potential of the strain in the ointment was assessed on 3D RHE, and the skin corrosive potential was evaluated on RHE.
Results:
ATR04-484 comparably inhibited growth of both MRSA and MSSA in therapeutic and prophylactic settings. In a therapeutic setting, ATR04-484 inhibited MRSA growth by 1 log (90%) compared to untreated MRSA in both RHE and pig skin. In a prophylactic setting, ATR04-484 inhibited MRSA growth by approximately 5 logs on RHE and 2 logs on pig skin. Additionally, application of ATR04-484 reduced IL-36γ to a level comparable to untreated RHE. The effect was dose-dependent; application of 10
9
CFU/cm
2
of ATR04-484 showed more potent IL-36γ reduction compared to 10
8
CFU/cm
2
. The three toxicology assays indicate that ATR04-484 does not cause irritation or corrosion.
Conclusions:
In these preclinical studies, ATR-04-484 showed a promising preclinical profile for the treatment of EGFRi-induced dermal toxicity by significantly reducing
S. aureus
growth, completely ameliorating IL-36γ levels, and showing no safety concerns.
Clinical status
Pre-clinical
1 organization
Organization
Azitra