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| Ref Type | abstract | ||||||||||||
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| Authors | Jiajia Pan; Hongwang He; Li Li; Jun Wang; Xiaolin Wang; Kehua Fan; Hui Feng | ||||||||||||
| Title | Abstract LB227: ALK201, a first-in-class FGFR2b-targeting antibody-drug conjugate for patients with FGFR2b+ gastric cancer and other solid tumors | ||||||||||||
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| URL | https://aacrjournals.org/cancerres/article/85/8_Supplement_2/LB227/761829 | ||||||||||||
| Abstract Text | Abstract Background: Fibroblast growth factor receptor-2b (FGFR2b) is a receptor tyrosine kinase mainly expressed on epithelial cells and involved in numerous cellular functions. Overexpression of FGFR2b in solid tumors, especially gastric cancer, is associated with poor prognosis, making it a compelling candidate for targeting therapy. Methods: ALK201 consists of a humanized high-affinity FGFR2b-targeting antibody, a proprietary, hydrophilic and cleavable linker, and Exatecan, a topoisomerase I inhibitor. Binding properties and mechanism of actions of ALK201 were evaluated in a panel of in vitro studies. ALK201 was evaluated for in vivo anti-tumor effects in xenograft model of gastric cancer cell line SNU-16 and patient-derived xenograft (PDX) models across multiple tumor types. Pharmacokinetic (PK) profile of ALK201 was characterized in rats and non-human primates (NHP). GLP toxicology studies of AK201 were also conducted in rats and NHPs. Results: ALK201 bound human FGFR2b specifically and cross-reacted with FGFR2b from cynomolgus monkey, mouse and rat. ALK201 blocked FGF7/10-FGFR2b interaction and inhibited downstream phospho-ERK activation, comparable to Bemarituzumab. In addition, ALK201 demonstrated favorable antibody dependent cell mediated cytotoxicity (ADCC) on FGFR2b-expressing gastric cancer cells KATOIII with primary human NK cells. ALK201 showed efficient internalization, potent killing of FGFR2b+ tumor cells, and a strong bystander killing activity. ALK201 significantly inhibited tumor growth in SNU16 model, as well as in Bemarituzumab-resistant PDX models of gastric, breast and squamous non-small cell lung cancer. Moreover, ALK201 had a favorable PK profile in both rats and cynomolgus monkeys with limited payload shedding. ALK201 also exhibited a good safety profile in GLP toxicology studies, showing STD10>150 mg/kg in SD rats and HNSTD of 60 mg/kg in cynomolgus monkeys. The main adverse event profiles in monkeys included anemia, decreased erythrocytes in the bone marrow smears of some animals without significant abnormality in the histopathological examination of bone marrow, minimal to mild decrease cellularity of lymphocytes in the immune system, and minimal atrophy in eye cornea (only observed in the high dose group, 60 mg/kg). At the end of the recovery period, those abnormalities were fully recovered. Conclusions: In summary, preclinical results indicated that ALK201 is an effective candidate for the treatment of solid tumors expressing FGFR2b with a tolerable safety profile. The phase I/II clinical study including dose escalation and dose expansion to evaluate the safety, tolerability, PK and anti-tumor activity of ALK201 in adult participates with advanced solid tumor is ongoing (NCT06656390). Acknowledgments: We thank Dr. Sheng Yao for editorial assistance and his willingness to sponsor the abstract. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| ALK201 | ALK-201|ALK 201 | FGFR2 Antibody 5 | ALK201 is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting FGFR2b linked to exatecan, which inhibits FGFR2b signaling and potentially induces antibody-dependent cellular cytotoxicity and inhibits tumor growth (Cancer Res (2025) 85 (8_Supplement_2): LB227). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| FGFR2 positive | breast cancer | predicted - sensitive | ALK201 | Preclinical - Pdx | Actionable | In a preclinical study, ALK201 inhibited tumor growth in a patient-derived xenograft (PDX) model of FGFR2b-expressing breast cancer (Cancer Res (2025) 85 (8_Supplement_2): LB227). | detail... |
| FGFR2 positive | lung non-small cell carcinoma | predicted - sensitive | ALK201 | Preclinical - Pdx | Actionable | In a preclinical study, ALK201 inhibited tumor growth in a patient-derived xenograft (PDX) model of FGFR2b-expressing squamous non-small cell lung cancer (Cancer Res (2025) 85 (8_Supplement_2): LB227). | detail... |
| FGFR2 positive | stomach cancer | predicted - sensitive | ALK201 | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, ALK201 induced antibody-dependent cellular cytotoxicity in gastric cancer cells expressing FGFR2b in culture and inhibited tumor growth in a cell line xenograft and patient-derived xenograft (PDX) model (Cancer Res (2025) 85 (8_Supplement_2): LB227). | detail... |