Purple Biotech Presents New Data for its Novel Tri-Specific T Cell & NK Cell Engagers Antibody Platform

Purple Biotech Ltd. recently announced new data regarding its tri-specific antibody platform, CAPTN-3, which were presented at the 36th European Organization for Research and Treatment of Cancer, National Cancer Institute, American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics on October 25, 2024, in Barcelona, Spain.

“CAPTN-3 is a novel technology platform allowing Purple Biotech to develop a variety of new tri-specific antibodies to address different targets on tumors and different mechanisms to treat cancer patients. Our Investigational New Drug (IND) enabling work is aimed to reach first in human clinical studies with our lead candidate IM1240 potentially by 2026,” said Gil Efron, Purple Biotech CEO. “Development of this differentiated platform allows us to potentially offer partners and patients additional antibodies to treat different cancer types.”

CAPTN-3 is a novel platform technology of conditionally activated tri-specific antibodies engaging both T cells and NK cells to target cancers expressing Tumor Associated Antigen (TAA) (αCD3xαTAAxαNKG2A) to induce a strong and selective immune response against the tumor. The addition of the NK engager aims to enhances the tumor-killing activity, providing a key differentiation for more sustained and potent anti-tumor effects. The anti-NKG2A arm also acts as a checkpoint inhibitor enabling simultaneous NK and T-cell activation. This scaffold is designed to be activated only at the tumor microenvironment (TME) to improve the safety profile and extend the therapeutic index. The capped-αCD3 is cleaved by multiple TME-specific proteases, increasing the likelihood of activation by various tumor types. To further extend the capped tribody half-life, human serum albumin is included. CAPTN-3 leverages a plug and play scaffold system providing a flexible design to easily swap and integrate various antibodies to target a wide range of diseases.

The platform’s lead compound IM1240 (aCD3xa5T4xaNKG2A) targets 5T4, a TAA expressed in a variety of solid tumors and which is correlated with advanced disease, increased invasiveness, and poor clinical outcome.

“Unleashing both innate and adaptive immune subsets against the tumor through potential engagement of both T cells and NK cells to the tumor, accompanied by NKG2A:HLA-E checkpoint blockage enabling simultaneous activation of NK cell and highly cytotoxic NKG2A⁺ T cell subsets, is suggested as a powerful mechanism of CAPTN-3 to enhance the anti-tumor activity, and differentiates this approach from others in the field. Our CAPTN-3 platform’s lead candidate, IM1240, was found to induce enhanced and synergistic anti-tumor activity in a clinically-relevant PDE assay of a 5T4-expressing biopsy, as compared to the T cell engager or the NK cell engager bispecific derivatives. CAPTN-3’s conditional activation mechanism, including a selective capping cleavage by TME proteases and TAA dependency, potentially improve safety and efficacy, and therefore result in a wider therapeutic window. The advantages of the cleavable capping technology, in aspects of efficacy, drug exposure, and safety are demonstrated in this poster,” stated Purple Biotech’s VP Research and Development, Dr. Hadas Reuveni. “IM1240’s target, 5T4, which associates with advanced disease, increased invasiveness and poor prognosis, is an attractive target for a variety of solid cancers.”

Purple Biotech’s poster titled “CAPTN-3: A novel platform of conditionally activated T cell and NK cell engagers,” which can be viewed HERE, presented the following:

• The lead compound, IM1240 demonstrated high affinity binding towards CD3 & NKG2A proteins and CD3 & NKG2A expressing cells, while no binding was detected using the mutated versions of the tribody, indicating specificity. The synergistic effects of the αCD3 and αNKG2A arms in suppressing 5T4⁺ non-small cell lung cancer (NSCLC) patient-derived explant (PDE) at 10nM were demonstrated, emphasizing CAPTN-3’s potential advantage in a clinically-relevant biological assay. A dose-dependent effect of IM1240 was shown.
• Sustained tumor regression in triple negative breast cancer humanized mice was demonstrated for the capped tribody, which was superior to the uncapped tribody. No effect was shown with the non-cleavable capped tribody whose CD3 binding function is irreversibly blocked.
• Cytotoxic effect and binding to CD3 was fully recovered following capping cleavage.
• PBMC-mediated cytotoxicity against 5T4⁺ cancer cells was demonstrated at picomolar EC50 while no effect was observed in 5T4^– cancer cells.
• IM1240 and non-capped tribody inhibited NKG2A-HLA-E interaction in a dose-dependent manner, while NKG2A mutated tribody had no effect.
• NK cell mediated cytotoxicity against HLA-E expressing cancer cells was demonstrated, while NKG2A mutated tribody had no effect.
• A cytokine release assay from hPBMC showed a 5T4⁺ cancer cell dependency and was inhibited by the cap, showing superior safety profile.
• Plug and Play abilities of the platform were demonstrated through different tribodies targeting 5T4 (αCD3xα5T4xαNKG2A), EGFR (αCD3xαEGFRxαNKG2A) and NKG2D (αCD3xα5T4xαNKG2D) which demonstrated low nM and selective binding to cells overexpressing the target, and efficient PBMC and NK mediated cytotoxicity.

Purple Biotech Ltd. (NASDAQ/TASE: PPBT) is a clinical-stage company developing first-in-class therapies that seek to overcome tumor immune evasion and drug resistance. The Company’s oncology pipeline includes CM24, NT219 and IM1240. CM24 is a humanized monoclonal antibody that blocks CEACAM1, that supports tumor immune evasion and survival through multiple pathways. CEACAM1 on tumor cells, immune cells and neutrophils extracellular traps is a novel target for the treatment of multiple cancer indications. As a proof of concept of these novel pathways, the Company is advancing CM24 as a combination therapy with anti-PD-1 checkpoint inhibitors in a Phase 2 study for the treatment of pancreatic ductal adenocarcinoma (PDAC). The Company has entered into a clinical collaboration agreement with Bristol Myers Squibb for the Phase 2 clinical trials to evaluate the combination of CM24 with the PD-1 inhibitor nivolumab in addition to chemotherapy. NT219 is a dual inhibitor, novel small molecule that simultaneously targets IRS1/2 and STAT3. A Phase 1 dose escalation study was concluded as a monotherapy and in combination with cetuximab in which NT219 demonstrated anti-tumor activity in combination with cetuximab in second line patients with recurrent and/or metastatic SCCHN (R/N SCCHN). The Company is advancing CAPTN-3, a preclinical platform of conditionally-activated tri-specific antibody that engages both T cells and NK cells to induce a strong, localized immune response within the tumor microenvironment. The cleavable capping technology confines the compound’s therapeutic activity to the local tumor microenvironment, and thereby potentially increases the anticipated therapeutic window in patients. The third arm specifically targets the Tumor Associated Antigen (TAA). The technology presents a novel mechanism of action by unleashing both innate and adaptive immune systems to induce an optimal anti-tumoral immune response. IM1240 is the first tri-specific antibody in development that targets 5T4 expressed in a variety of solid tumors and which is correlated with advanced disease, increased invasiveness and poor clinical outcomes. The Company’s corporate headquarters are located in Rehovot, Israel. For more information, visit https://purple-biotech.com/.