WPD101- targeting brain cancers with WPD101 molecule
WPD101 is a unique drug cocktail composed of two immunotoxins targeting IL-13RA2 (WPD101a) and EphA2 (WPD101b) receptors simultaneously. Immunotoxins are fusion proteins comprised of a toxic moiety and a targeting moiety.
This strategy guarantees specific drug administration to the majority of GBM cells. Furthermore, to increase tissue distribution, minimize possible side effects, and overcome BBB difficulties, Convection Enhanced Delivery (CED) of WPD101 directly to the brain tumor will be applied (Debinski and Tatter, 2009).
WPD101 is currently in the preclinical stage of development. Its consistent anticancer properties are demonstrated and validated in dogs with spontaneous GBM resembling GBM in human patients. The canine model of spontaneous gliomas represents the closest translational model to human diseases and provides a potentially more clinically relevant assessment of potential efficacy in human trials regarding biological and technological aspects of treatment. Canine gliomas and human GBM cells overexpress tumor-associated IL-13RA2 and EphA2 receptors that are not present in normal brain cells. IL-13RA2 and EphA2 are conjointly present in >90% of patients and dogs with GBM. The preliminary preclinical study in mice led to the safe dose determination on the 50 ug/ml (repeated dose study).
Future
In addition to the aforementioned CED method, alternative methods for intracerebral delivery of the WPD101a immunotoxin are currently being developed, including the use of hydrogel formulations and implants made of biocompatible polymers.
INTERCEPTOR – targeting brain cancers with WPD401 molecule
WPD401 is an advanced multivalent targeted cytotoxin towards four cancer-associated cell-surface receptors: IL-13Ra2, EPHA2, EPHA3, and EPHB2. The molecule is composed of a multitargeting ligand chemically conjugated to a toxic payload.
Upon binding to one of the four receptors, the cytotoxin is internalized via endocytosis where it releases the cytotoxic agent. The released chemical is a potent microtubule disrupting agent which triggers cancer cell apoptosis, destroying a tumor.
WPD401 was designed to target glioblastoma cells, regardless of their inherent heterogeneity. WPD401 selectively and potently eliminates cancer cells, including glioma stem-like cells, infiltrating cells, neo-vasculature, and immunosuppressive tumor microenvironment. IL-13Ra2, EPHA2, EPHA3, and EPHB2 tumor-associated receptors are conjointly found in nearly every grade IV glioma and constitute very attractive targets for multivalent monotherapy with WPD401. Thus, WPD401 may closely target all cases of glioblastoma. Even when one receptor is not present on a glioma cell, the cell will be still effectively targeted by the cytotoxin. Since the WPD401-targeted receptors may be associated with other tumors, their brain metastases could also potentially be targeted with the cytotoxin. WPD401 is an excellent candidate drug to effectively treat gliomas and other primary and metastatic brain tumors.
We were encouraged by the previous results of a related combination therapy approach with a mixture of two cytotoxins targeting IL-13Ra2 and EPHA2 receptors from preclinical model of spontaneous gliomas in dogs (2021). The treatment resulted in 50% clinically relevant responses. We postulate the introduction of combination therapies to obtain more comprehensive and durable responses.
Future
Our preclinical studies to date have confirmed the effectiveness of targeting the glioblastoma-associated receptors with WPD401 and its potent cytotoxicity. The ongoing transfer of manufacturing technology will advance the cytotoxin to further planned toxicokinetic and future human clinical trials.
WPD103- targeting brain cancers with WPD101 molecule
WPD103 is a radiopharmaceutical that relies on targeted interaction with receptors characteristic of cancer cells: IL-13RA2, while normal cells mainly exhibit expression of IL-13RA1 receptors. WPD Pharmaceuticals' groundbreaking solution involves the use of molecules - recombinant proteins: ligands (IL-13) linked to a radionuclides with targeted diagnostic potential.
Recombinant cytokines preferentially bind to receptors present on the membrane of cancer cells, allowing for the selective elimination of these cells using radiotherapy.
Future
WPD103 is currently in the preclinical stage of development. Based on studies conducted on the WPD101 in vitro cell line model and canine glioma model, WPD103 appears to be a potential diagnostic tool for GBM in humans. The completion of the project will lead to the development of an innovative tool for early detection of cancer cells. In the next step, targeted elimination will be possible, providing an alternative to standard, less effective therapy. The evolving solution aligns with a new strategy of theranostic cancer treatment, which combines diagnostic and therapeutic elements.
Meteor - targeting breast cancer with WPD401 molecule
WPD401 is an advanced multivalent targeted cytotoxin towards four cancer-associated cell-surface receptors: IL-13Ra2, EPHA2, EPHA3, and EPHB2. The molecule is composed of a multitargeting ligand chemically conjugated to a toxic payload.
Upon binding to one of the four receptors, the cytotoxin is internalized via endocytosis where it releases the cytotoxic agent. The released chemical is a potent microtubule disrupting agent which triggers cancer cell apoptosis, destroying a tumor.
WPD401 was initially designed for selective and potent targeting of glioblastoma cells, including glioma stem-like cells, tumor neo-vasculature, and immunosuppressive microenvironment. However, it was rapidly discovered that WPD401 molecule is also highly cytotoxic to breast cancer. The presence of targeted IL-13Ra2, EPHA2, EPHA3, EPHB2 receptors were detected in patients-derived primary and metastatic breast cancer (BC) samples. Furthermore, IL-13Ra2 presence has been previously well documented in triple-negative breast cancers (TNBC) but not in normal breast tissue. Preclinical in vitro studies, showed significant cytotoxic effect of WPD401 against breast cancers cells, including triple-negative forms, as well as its lung and brain metastases. These promising data prompted us to launch a Meteor development line to explore the potential applicability of WPD401 to treat breast cancers.
A preliminary toxicity study was conducted in mice, which received WPD401 by intravenous (IV) or intracranial (IC) bolus injections confirmed drug safety. No weight loss and other systemic or neurotoxicity was observed. A preliminary proof-of-concept study demonstrated antitumor WPD401 activity, that significantly decreasing tumor volume compared to the control mice.
Future
The ongoing transfer of manufacturing technology of WPD401 will advance the cytotoxin to further preclinical and clinical studies.