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Ref Type Abstract
PMID
Authors Chansik Kim; Jin Gu Cho; TaeMin Wi; Jiwoo Moon; Han-Jik Ko; Jina Lee; Jin Woo Park; Yeonjy Lee; Sanghee Kim; Jin-Ock Kim; Jaeyoung Song; Sun-Hwa Lee; Sang Gyu Park
Title Abstract 3142: NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 84 6_supplement March 22 2024 3142 Cancer Res
URL https://aacrjournals.org/cancerres/article/84/6_Supplement/3142/735445/Abstract-3142-NN3201-a-novel-c-Kit-targeting-ADC
Abstract Text Abstract c-Kit (CD117) is a type III receptor tyrosine kinase (RTK), which is known to be activated upon binding to its cognate ligand stem cell factor (SCF) to induce critical signaling pathways involved in cell proliferation, survival, and differentiation. Indicative of poor prognosis, overexpression and activating mutations of c-Kit have been implicated in a variety of human cancers including small cell lung cancer (SCLC), gastrointestinal stromal tumors (GIST), and acute myelogenous leukemia (AML). While imatinib, a small molecule c-Kit inhibitor, has been a beneficial treatment for GIST, resistance eventually develops to the drug, moreover, shows limited efficacy in c-Kit overexpressing tumors such as SCLC. Herein, we developed NN3201, a novel c-Kit targeting antibody-drug conjugate (ADC), comprised of fully human 2G4 antibody with a picomolar binding affinity to c-Kit and cytotoxic monomethyl auristatin E (MMAE) as the payload. NN3201 displayed potent in vitro cytotoxicity in various wild-type and mutant c-Kit positive SCLC and GIST cell lines with IC50 in the nanomolar range. In addition, NN3201 was rapidly internalized and inhibited c-Kit-mediated signaling., NN3201 treatment resulted in the increased proportions of the sub G1 and G2/M in the c-Kit positive cancer cell lines, indicating that release of MMAE induced cell cycle arrest. Moreover, bystander effect was confirmed by co-culturing c-Kit high and negative cell lines. Most importantly, in mouse xenograft models, NN3201 showed a remarkable tumor growth inhibition of several wild type, mutant c-Kit positive, and imatinib resistant SCLC and GIST cell lines. Enhanced anti-tumor activity and delayed tumor growth were observed in an SOC-treated (etoposide and carboplatin) SCLC xenograft model, by NN3201 in comparison to second line SOC (topotecan or irinotecan). In the GLP study, repeated intravenous administration of NN3201 was well tolerated at all doses (0.5, 1, 2 mg/kg Q3Wx3) without unscheduled death. Dose-dependent, yet transient, cytotoxicity of NN3201 was observed in the bone marrow. We confirmed HNSTD (Highest Non-Severely Toxic Dose) of NN3201 to be 2 mg/kg through exploratory and GLP repeat dose toxicity studies as no serious irreversible toxicity was observed. Accumulating data suggest that NN3201 is a promising therapeutic alternative for the treatment of SCLC and GIST regardless of wild-type or activating mutations in c-Kit.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
NN3201 NN3201 2 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
NN3201 NN 3201|NN-3201 NN3201 is an antibody-drug conjugate (ADC) comprising an antibody targeting KIT linked to monomethyl auristatin E (MMAE), which potentially induces cytotoxicity against KIT-expressing tumor cells and inhibits tumor growth (Cancer Res (2024) 84 (6_Supplement): 3142).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT positive lung small cell carcinoma predicted - sensitive NN3201 Preclinical - Cell line xenograft Actionable In a preclinical study, NN3201 induced cytotoxicity and cell cycle arrest in KIT-positive small cell lung cancer cell lines in culture, and inhibited tumor growth in a cell line xenograft model (Cancer Res (2024) 84 (6_Supplement): 3142). detail...
KIT positive gastrointestinal stromal tumor predicted - sensitive NN3201 Preclinical - Cell line xenograft Actionable In a preclinical study, NN3201 induced cytotoxicity and cell cycle arrest in KIT-positive gastrointestinal stromal tumor cell lines in culture, and inhibited tumor growth in a cell line xenograft model (Cancer Res (2024) 84 (6_Supplement): 3142). detail...