Amivantamab
(Synonyms: JNJ-61186372) 目录号 : GC67749Amivantamab (JNJ-61186372) 是一种人源 EGFR-MET 双特异性抗体，具有免疫抗癌活性。Amivantamab 可以抑制配体结合，促进受体-抗体复合物的内吞作用和降解，并诱导巨噬细胞的 Fc 依赖性胞吞作用和自然杀伤细胞的抗体依赖性细胞毒性。
Cas No.:2171511-58-1
Sample solution is provided at 25 µL, 10mM.
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Amivantamab (JNJ-61186372) is a human EGFR-MET bispecific antibody with immune anticancer activity. Amivantamab inhibits ligand binding, promotes endocytosis and degradation of receptor-antibody complexes, and induces Fc-dependent cytokinesis in macrophages and antibody-dependent cytotoxicity in natural killer cells[1].
Amivantamab (JNJ-61186372)(0.05-1 mg/mL) 导致 Ba/F3 细胞活力显着且剂量依赖性降低，EGFR 下游信号通路磷酸化 EGFR (pEGFR)、磷酸化 AKT (pAKT)、磷酸化 ERK (pERK) 和磷酸化 S6 (pS6) 也显着降低[2]。
Amivantamab (JNJ-61186372) (i.p, 30 mg/kg, twice a week, 15 days) 可以有效减小雌性无胸腺 BALB-c/nu 小鼠肿瘤体积，具有体内抗肿瘤作用[2]。
[1]. Keunchil Park, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402.
[2]. Jiyeon Yun, et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models ofEGFRExon 20 Insertion-Driven NSCLC. Cancer Discov. 2020 Aug;10(8):1194-1209.
| Cas No. | 2171511-58-1 | SDF | Download SDF |
| 别名 | JNJ-61186372 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C for 1 years. | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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Amivantamab: First Approval
Drugs 2021 Jul;81(11):1349-1353.PMID:34292533DOI:10.1007/s40265-021-01561-7.
Amivantamab (amivantamab-vmjw; Rybrevant™), a bispecific monoclonal antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (MET), is being developed by Janssen Biotech for the treatment of non-small cell lung cancer (NSCLC). On 21 May 2021, Amivantamab received its first approval in the USA for the treatment of adult patients with locally advanced or metastatic NSCLC harbouring EGFR Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Amivantamab is in preregistration for NSCLC in the EU, Australia, Japan, Canada, Switzerland and China. This article summarizes the milestones in the development of Amivantamab leading to this first approval for NSCLC.
Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study
J Clin Oncol 2021 Oct 20;39(30):3391-3402.PMID:34339292DOI:10.1200/JCO.21.00662.
Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg Amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.
MARIPOSA: phase 3 study of first-line Amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer
Future Oncol 2022 Feb;18(6):639-647.PMID:34911336DOI:10.2217/fon-2021-0923.
Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated efficacy in patients with EGFR-mutant non-small-cell lung cancer; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS study (NCT02609776), Amivantamab in combination with lazertinib, a potent, brain-penetrant third-generation EGFR TKI, demonstrated antitumor activity in the treatment-naive and osimertinib-relapsed setting. Here the authors present the methodology for the MARIPOSA study (NCT04487080), a phase 3, multicenter, randomized study designed to compare the efficacy and safety of Amivantamab and lazertinib combination therapy versus single-agent osimertinib as first-line treatment for EGFR-mutant non-small-cell lung cancer.
Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC
Cancer Discov 2020 Aug;10(8):1194-1209.PMID:32414908DOI:10.1158/2159-8290.CD-20-0116.
EGFR exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of Amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft models harboring diverse Exon20ins were used to characterize the antitumor mechanism of Amivantamab. Amivantamab inhibited proliferation by effectively downmodulating EGFR-MET levels and inducing immune-directed antitumor activity with increased IFNγ secretion in various models. Importantly, in vivo efficacy of Amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins-targeted TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work. These findings provide mechanistic insight into the activity of Amivantamab and support its continued clinical development in Exon20ins patients, an area of high unmet medical need. SIGNIFICANCE: Currently, there are no approved targeted therapies for EGFR Exon20ins-driven NSCLC. Preclinical data shown here, together with promising clinical activity in an ongoing phase I study, strongly support further clinical investigation of Amivantamab in EGFR Exon20ins-driven NSCLC.This article is highlighted in the In This Issue feature, p. 1079.
Discovery of Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET
J Biol Chem 2021 Jan-Jun;296:100641.PMID:33839159DOI:10.1016/j.jbc.2021.100641.
A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate Amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of Amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain-Sema engagement. The Amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, Amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, Amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.