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Development of SDP0505: a first-in-class HER3 × c-Met bispecific ADC, demonstrates potent antitumor activity in EGFR
Li-Min Wang1, Changyong Yang1, Simeng Chen1
1Jiangsu Hengrui Pharmaceuticals Co., Ltd, Jiangsu 222047, China.
Background:
Despite the success of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance remains an unmet need. Although human epidermal growth factor receptor 3 (HER3) and c-Met upregulation are key mechanisms of this resistance, the rationale for simultaneously targeting both to overcome this challenge remains unexplored.
Methods:
HER3 and c-Met expression were evaluated by immunohistochemistry in 270 clinical samples, including EGFR TKI-resistant NSCLC, lung adenocarcinoma (LUAD), gastric cancer, and colorectal cancer (CRC). The binding affinity of SDP0505 was measured by surface plasmon resonance and enzyme-linked immunosorbent assay, internalization was monitored using Incucyte, and in vitro cytotoxicity was assessed via CellTiter-Glo assay. The in vivo anti-tumor activities were investigated in cell-derived and patient-derived xenograft (PDX) models. Pharmacokinetics and repeated-dose toxicity were studied in cynomolgus monkeys.
Results:
Immunohistochemical analyses revealed spatial colocalization of HER3 and c-Met in EGFR TKI-resistant NSCLC specimens. Furthermore, high co-expression was observed in 58% of EGFR-mutant LUAD and 95% of CRC cases. Consequently, SDP0505 was developed with optimal antigen-binding affinity and antibody format through comprehensive screening. In HER3/c-Met dual-positive cell lines, SDP0505 demonstrated enhanced cell binding and internalization over the in-house synthesized U3-1402 analog. Superior in vivo antitumor efficacy was also observed in multiple NSCLC and CRC models, including EGFR TKI-resistant PDX models. Moreover, SDP0505 exhibited favorable pharmacokinetic and safety profiles in cynomolgus monkeys.
Conclusions:
SDP0505 represents a novel HER3 × c-Met ADC with superior internalization and anti-tumor activity in preclinical models, especially in EGFR TKI-resistant PDX models. These results supported the initiation of a Phase I clinical trial in China.
Insights
A novel antibody-drug conjugate, SDP0505, targets both HER3 and c-Met to overcome resistance in EGFR-mutant non-small cell lung cancer. This dual-targeting approach shows promising anti-tumor activity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acquired resistance to third-generation EGFR TKIs is a significant challenge in EGFR-mutant NSCLC.
- Upregulation of HER3 and c-Met are identified as key resistance mechanisms.
- Simultaneous targeting of HER3 and c-Met for resistance remains unexplored.
Purpose of the Study:
- To investigate the potential of dual HER3 and c-Met targeting to overcome EGFR TKI resistance.
- To develop and evaluate a novel antibody-drug conjugate (ADC), SDP0505, targeting both HER3 and c-Met.
Main Methods:
- Immunohistochemistry to assess HER3 and c-Met expression in clinical samples (NSCLC, LUAD, gastric, CRC).
- Biophysical assays (SPR, ELISA) to measure binding affinity of SDP0505.
- Cell-based assays (Incucyte, CellTiter-Glo) to evaluate internalization and in vitro cytotoxicity.
- In vivo studies using xenograft models (cell-derived and PDX) and pharmacokinetic/toxicity assessments in non-human primates.
Main Results:
- Spatial colocalization and high co-expression of HER3 and c-Met were observed in EGFR TKI-resistant NSCLC, LUAD, and CRC.
- SDP0505 demonstrated superior binding, internalization, and in vitro cytotoxicity compared to an analog in dual-positive cell lines.
- SDP0505 exhibited significant in vivo anti-tumor efficacy in various models, including EGFR TKI-resistant PDX models.
- Favorable pharmacokinetic and safety profiles were observed in cynomolgus monkeys.
Conclusions:
- SDP0505 is a novel HER3 x c-Met ADC with potent internalization and anti-tumor activity.
- The ADC shows particular promise in EGFR TKI-resistant PDX models.
- Clinical trials (Phase I) are warranted and have been initiated based on these preclinical findings.
