On June 22, 2023 Parthenon Therapeutics, a precision oncology company discovering and developing a novel class of therapies that reprogram the tumor microenvironment (TME), reported that the Journal for ImmunoTherapy of Cancer (JITC) has published results from a collaboration between Parthenon Therapeutics, The University of Texas Health Center at Houston (UTHealth Houston) and George Washington University, demonstrating that PRTH-101 potently inhibits the adhesion of collagen receptor discoid in domain receptor-1 (DDR1)-expressing cancer cells to collagen substrates and DDR1 autophosphorylation induced by collagen (Press release, Parthenon Therapeutics, JUN 22, 2023, View Source [SID1234632864]).

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The article entitled, "A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer," describes the humanization of PRTH-101 and the mechanism by which the drug candidate binds to its target to inhibit DDR1. The publication is now available online on the JITC website.

Key Publication Highlights

Structural studies, including a PRTH-101/DDR1 co-crystal structure, identified the PRTH-101 epitope on DDR1
Culturing DDR1-expressing human cancer cells with PRTH-101 inhibited DDR1 autophosphorylation induced by collagen and the shedding of DDR1 fragments from the cell surface
PRTH-101 demonstrated the ability to potently inhibit the adhesion of DDR1-expressing cancer cells to collagen substrates, disrupting the physical barrier formed by aligned collagen fibers in tumors
The ability of PRTH-101 to inhibit functions of the extracellular component of DDR1 differentiates PRTH-101 from DDR1 kinase inhibitors
"Our collaboration with UTHealth Houston and George Washington University has yielded great insight into the capabilities of PRTH-101 as well as demonstrated the role of DDR1 in promoting immune exclusion in cancers," said J. Paul Eder, MD, Chief Medical Officer of Parthenon Therapeutics. "This study reinforces the development of PRTH-101 as a cancer therapeutic, and also sheds light on a new therapeutic strategy to modulate collagen alignment in the tumor ECM for enhancing antitumor immunity."

Parthenon recently initiated a Phase 1 first-in-human clinical trial for its lead candidate PRTH-101 in patients with advanced solid tumors (NCT05753722).

About PRTH-101

PRTH-101 is a therapeutic antibody that specifically binds to and blocks DDR1, a protein expressed on tumor cells that binds collagen to make a minimally permeable physical barrier blocking immune cells from interacting with and attacking tumor cells. Thus, these "immune cell-excluded" solid tumors are resistant to attack by the immune system (as well as other existing therapies). By disabling DDR1, the collagen fibers lose alignment and loosen, creating gaps in the tumor barrier, thus allowing T cells to enter and attack the tumor. The creation of DDR1-directed collagen alignment does not appear to have a normal physiological surrogate and may therefore be unique to pathologies such as neoplasia, potentially allowing for relatively safe interventions. Thus, blockade of DDR1 represents a unique and "orthogonal" approach to stimulating the immune-based antitumor activity, and such blockade shows both single agent anti-tumor activity as well as marked augmentation of immunity enhanced by PD-1 blockade.

Tumor types which show particularly high levels of DDR1-associated collagen barriers include colorectal, ovarian, and non-small cell lung cancer. Currently, there are no approved drugs that target DDR1.