Unmet Need
In the U.S., approximately 16% of non-small cell lung cancer (NSCLC) cases harbor epithelial growth factor receptor (EGFR) mutations, with insertions at exon 20 (EGFRex20ins) accounting for 12% of those mutations. Patients with EGFRex20ins mutations have poorer outcomes than those with more common EGFR mutations, such as exon 19 deletions. There remains a significant unmet need for therapies targeting EGFRex20ins mutations in NSCLC that are safer and more effective.
Unmet Need
A hallmark of cancer is the ability to avoid destruction by immune cells. Cancer cells develop escape mechanisms that can render them invisible to the human immune system. This immune evasion enables unrestricted tumor growth and potential metastasis. There is a significant unmet need for treatments that can help overcome immune-evasion mechanisms employed by tumors.
Based on preclinical models, CLN-619 is a potential first-in-class MICA/MICB-directed IgG1 antibody that restores the MICA/ MICB-NKG2D axis to promote NK-mediated tumor cell lysis. MHC class I chain-related proteins A and B (MICA/MICB) are proteins found on the surface of stressed cells and serve as a warning flag to the organism that the cell is damaged, targeting the flagged cells for elimination by immune cells. Cell stressors that activate MICA/MICB include viral infection, genotoxic stress, and malignant transformation. MICA/MICB are minimally expressed on normal cells and are upregulated in most solid tumor types and hematologic malignancies.
In cancer patients, tumor cells can escape natural killer group 2 member (NKG2D)-mediated lysis by shedding MICA/MICB from the cell surface via proteases present in the tumor microenvironment. CLN-619 restores the MICA/MICB pathway to engage both innate and adaptive immune cells and exerts its effects through multiple mechanisms:
Development Plan
About CLN-418
CLN-418/HBM7008 is the only B7H4 x 4-1BB bispecific immune activator in clinical studies. Both B7H4 and 4-1BB have been targets of high interest and both have been evaluated clinically. Their distinct biology and mechanisms of action provide strong rationale to combine them as a bispecific antibody. B7H4 is an attractive tumor associated antigen (TAA) highly expressed on multiple tumor types, including triple negative breast cancer, ovarian cancer and lung cancer, while expression on normal tissue is low. A coinhibitory immune checkpoint with PD-L1 in the B7 family, B7H4 has minimal overlap with PD-L1 expression. Targeting B7H4 has the potential to address tumor types for which PD-L1-based immunotherapies have exhibited limited efficacy.
4-1BB is a key costimulatory molecule for both T- and NK-cell engagement and is being studied in multiple clinical programs. However, safety concerns such as hepatic toxicity remain despite the biological validation of the 4-1BB pathway. Conditional activation of 4-1BB in the tumor microenvironment that is dependent on B7H4 expression presents a novel approach to harness the potential of both targets. CLN-418/HBM7008, with strict TAA crosslinking dependent T cell activation, can potentially translate to better safety and a more favorable therapeutic window. The ongoing Phase 1 trial (NCT05306444) is an open-label, multicenter study evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of CLN-418/HBM7008 administered intravenously in patients with advanced solid tumors. The study, which is expected to enroll up to 108 subjects, aims to identify a maximum tolerated dose and a recommended Phase 2 dose of CLN-418/HBM7008. Initial clinical data from this study could be available in 2024.
Unmet Need
While checkpoint inhibitors have revolutionized immuno-oncology, only a minority of patients respond, often due to the tumor being "cold," which means it lacks an appreciable number of infiltrated, tumor-specific T cells. For several decades, preclinical researchers and clinical investigators have characterized the powerful role interleukin (IL)-2 and IL-12 play in stimulating the immune response to cancer and turning the tumor "hot." Previous attempts to administer IL-2 and IL-12 directly into the tumor have failed to improve efficacy due to leakage of drug from the injection site. Because of the systemic toxicities of both IL-2 and IL-12, delivery directly into the tumor is theoretically attractive as long as an effective retention strategy is leveraged.
Asset Potential
CLN-617 is a potential first-in-class cytokine therapy candidate for intratumoral injection and is the first to combine IL-2 and IL-12 in a single molecule. CLN-617 is effectively retained in tumor tissue in preclinical animal models to avoid systemic toxicity. Local administration of CLN-617 promotes broad systemic immunosurveillance, potentially enabling the treatment of advanced disease, including mediating the regression of non-injected distal tumors and generating a memory of T cell responses to enhance long-term survival. Collagen is the major component of the tumor microenvironment; binding to collagen helps keep CLN-617 in the tumor.
Development Plan
In ongoing Phase 1/2a study, zipalertinib (CLN-081/TAS6417) demonstrated promising efficacy in heavily pretreated patients, including patients who progressed on treatment with EGFR tyrosine kinase inhibitors (TKIs), with favorable safety and tolerability profile. Results are encouraging in heavily pretreated patients, including those who progressed with other EGFR TKI. The safety profile is amenable for long-term treatment at doses <150mg BID. Zipalertinib (CLN-081/TAS6417) demonstrates the potential to become a new standard of care to treat NSCLC harboring EGFRex20ins mutations.