BACKGROUNDAdvances in antibody engineering provide strategies to construct recombinant antibody-like molecules with modified pharmacokinetic properties. Multermerization is one strategy that has been used to produce antibody-like molecules with two or more antigen binding sites. Multimerization enhances the functional affinity (avidity) and can be used to optimize size and pharmacokinetic properties. Most multimerization strategies involve genetically fusing or non-covalently linking antibody fragments using oligomerization domains. Recent studies have defined guidelines for producing antibody-like molecules with optimal tumor targeting properties, which require intermediates size (70-120 kDa) and bi- or tri-valency.RESULTSWe described a highly modular antibody-engineering platform for rapidly constructing synthetic, trivalent single chain variable fragments (Tri-scFv) using the SpyCatcher/SpyTag protein ligase system. We used this platform to construct an anti-human epidermal growth factor receptor 3 (HER3) Tri-scFv. We generated the anti-HER3 Tri-scFv by genetically fusing a SpyCatcher to the C-terminus of an anti-HER3 scFv and ligating it to a synthetic Tri-SpyTag peptide. The anti-HER3 Tri-scFv bound recombinant HER3 with an apparent K_D of 2.67 nM, which is approximately 12 times lower than the K_D of monomeric anti-HER3 scFv (31.2 nM). Anti-HER3 Tri-scFv also bound endogenous cell surface expressed HER3 stronger than the monomer anti-HER3 scFv.CONCLUSIONWe used the SpyTag/SpyCatcher protein ligase system to ligate anti-HER3 scFv fused to a SpyCatcher at its C-termini to a Tri-SpyTag to construct Tr-scFv. This system allowed the construction of a Tri-scFv with all the scFv antigen-binding sites pointed outwards. The anti-HER3 Tri-scFv bound recombinant and endogenously expressed HER3 with higher functional affinity (avidity) than the monomeric anti-HER3 scFv. The Tri-scFv had the size, valency, and functional affinity that are desired for therapeutic and imaging applications. Use of the SpyTag/SpyCatcher protein ligase system allows Tri-scFvs to be rapidly constructed in a simple, modular manner, which can be easily applied to scFvs or other antibody fragments targeting other antigens.

2018-12-01·Breast Cancer Research1区 · 医学

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers

1区 · 医学

ArticleOA

作者: Hobeika, Amy C ; Spector, Neil ; Osada, Takuya ; Morse, Michael A ; Clay, Timothy M ; Lyerly, H Kim ; Chen, Wei ; Hartman, Zachary C ; Diniz, Marcio A ; Gwin, William R ; Wei, Junping ; Lei, Gangjun

BACKGROUNDUpregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3.METHODSSerum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers.RESULTSHER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo.CONCLUSIONSIn addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.

2016-05-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Population pharmacokinetic analysis of patritumab, a HER3 inhibitor, in subjects with advanced non-small cell lung cancer (NSCLC) or solid tumors

4区 · 医学

Article

作者: Chen, Shuquan ; Yoshiba, Satoshi ; Jansen, Mendel ; Mendell, Jeanne ; Matsushima, Nobuko

PURPOSEThe purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets human epidermal growth factor receptor 3.METHODSA total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling.RESULTSPatritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing.CONCLUSIONSThe PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.

项与 Anti-Her3 therapy(Band Therapeutics, LLC) 相关的新闻（医药）

2023-09-10

·BioSpace

Patritumab Deruxtecan Demonstrated Clinically Meaningful and Durable Responses in Patients with EGFR-Mutated Metastatic Non-Small Cell Lung Cancer in HERTHENA-Lung01 Phase 2 Trial

An objective response rate of 29.8% was observed with patritumab deruxtecan in heavily pretreated patients BLA submission in U.S. planned for the second half of fiscal year 2023 TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Results from the HERTHENA-Lung01 phase 2 trial showed that patritumab deruxtecan (HER3-DXd) demonstrated clinically meaningful and durable responses in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) following disease progression with an EGFR TKI and platinum-based chemotherapy. These data were presented today during an oral presentation (OA05.03) at the 2023 World Conference on Lung Cancer (#WCLC23) and simultaneously published in the Journal of Clinical Oncology. Patritumab deruxtecan is a specifically engineered potential first-in-class HER3 directed antibody drug conjugate (ADC) designed using Daiichi Sankyo’s (TSE: 4568) proprietary DXd ADC technology. NSCLC accounts for approximately 85% of all lung cancers – 55% having distant spread at diagnosis – with EGFR-activating mutations occurring in 14% to 38% of all NSCLC tumors worldwide.1,2,3 After disease progression following treatment with an EGFR TKI and platinum-based chemotherapy, currently available therapies offer limited efficacy, highlighting the need for new approaches to improve outcomes.3,4 A confirmed objective response rate (ORR) of 29.8% (95% CI: 23.9-36.2) was observed with patritumab deruxtecan (5.6 mg/kg) in 225 patients with EGFR-mutated NSCLC as assessed by blinded independent central review (BICR). One complete response (CR), 66 partial responses (PRs) and 99 cases of stable disease (SD) were seen. A median duration of response (DOR) of 6.4 months (95% CI: 4.9-7.8) and a disease control rate (DCR) of 73.8% (95% CI: 67.5-79.4) were observed. Median progression-free survival (PFS) was 5.5 months (95% CI: 5.1-5.9) and median overall survival (OS) was 11.9 months (95% CI: 11.2-13.1) as of snapshot data cutoff of May 18, 2023. Efficacy outcomes were consistent across subgroups including a subset of 209 patients previously treated with a third-generation EGFR TKI and platinum-based chemotherapy. Anti-tumor activity with patritumab deruxtecan was observed across diverse mechanisms of EGFR TKI resistance and across a broad range of pretreatment tumor HER3 membrane expression. In a subset of 30 patients with brain metastases at baseline and no prior radiotherapy treatment, an intracranial ORR of 33.3% (95% CI: 17.3-52.8%) was observed as assessed by central nervous system (CNS) BICR. In these patients, nine intracranial CRs, one intracranial PR and 13 cases of SD were seen. A CNS DOR of 8.4 months (95% CI: 5.8-9.2) was observed. “The results from HERTHENA-Lung01 provide compelling evidence of efficacy of patritumab deruxtecan in heavily pretreated patients with advanced EGFR-mutated non-small cell lung cancer,” said Helena Yu, MD, Associate Attending Physician, Memorial Sloan Kettering Cancer Center. “The clinically meaningful efficacy observed across a broad range of HER3 expression and diverse mechanisms of EGFR TKI resistance as well as the anti-tumor activity seen in patients with brain metastases, underscore the potential of patritumab deruxtecan to become an important treatment option for a population of patients with lung cancer who have limited treatment options.” “Disease progression is inevitable in patients with previously treated and relapsed metastatic EGFR-mutated non-small cell lung cancer, reinforcing the need for new and innovative treatments across diverse mechanisms of resistance,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The results from HERTHENA-Lung01, coupled with early trial results, show that patritumab deruxtecan demonstrates clinically meaningful and durable responses, illustrating the potential of this HER3 directed antibody drug conjugate to become a new standard of care for this patient population with high unmet medical need. These data will support our ongoing discussions with health authorities including our planned submission in the U.S.” The safety pro patritumab deruxtecan observed in HERTHENA-Lung01 was consistent with previous clinical trials with a low rate (7.1%) of treatment discontinuation due to treatment-emergent adverse events (TEAEs) at the time of primary data cutoff of November 21, 2022. Grade 3 or higher TEAEs occurred in 64.9% of patients. The most common (>5%) grade 3 or higher TEAEs were thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%) and asthenia (5%). Twelve patients (5.3%) had confirmed treatment-related interstitial lung disease (ILD) as determined by an independent adjudication committee. The majority of ILD events were low grade with one grade 1 event and eight grade 2 events. Two grade 3, zero grade 4 and one grade 5 ILD event were observed. In HERTHENA-Lung01, 51% of patients (n=115) had a history of CNS metastases; 32% (n=72) and 33% of patients (n=75) had brain or liver metastases at baseline by BICR, respectively. In the trial, 63% (n=142) and 36% (n=82) of patients had either an EGFR exon 19 deletion or exon 21 L858R mutation detected at baseline, respectively, and one patient had both. Patients were heavily pretreated receiving a median of three prior lines of systemic therapy in the locally advanced/metastatic setting (range, 1-11), including platinum-based chemotherapy (100%), third generation EFGR TKI (93%) and immunotherapy (40%). As of the snapshot data cutoff of May 18, 2023, the median trial duration was 18.9 (14.9-27.5) months, and 13 patients were continuing to receive patritumab deruxtecan. Summary of HERTHENA-Lung01 Results Efficacy Measure Prior treatment with any EGFR TKI and platinum-based chemotherapy n=225 Subset with prior treatment with third-generation EGFR TKI and platinum-based chemotherapy n=209 Confirmed ORR, % (95% CI) 29.8% (23.9-36.2) 29.2.% (23.1-35.9) CR, n (%) 1 (0.4%) 1 (0.5%) PR, n (%) 66 (29.3%) 60 (28.7%) SD, n (%) 99 (44.0%) 91 (43.5%) PD, n (%) 43 (19.1%) 41 (19.6%) NE, n (%) 16 (7.1%) 16 (7.7%) DCR (95% CI), % 73.8% (67.5-79.4) 72.7% (66.2-78.6) DOR, median (95% CI), months 6.4 months (4.9-7.8) 6.4 months (5.2-7.8) PFS, median (95% CI), months 5.5 months (5.1-5.9) 5.5 months (5.1-6.4) OS, median (95% CI), months 11.9 months (11.2-13.1) 11.9 months (10.9-13.1) CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; ORR, objective response rate; OS, overall survival; PR, partial response; PFS, progression-free survival; PD, progressive disease; SD, stable disease. About HERTHENA-Lung01 HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase 2 trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR TKI and platinum-based chemotherapy. Patients were randomized 1:1 to receive 5.6 mg/kg (n=225) or an uptitration regimen (n=50). The uptitration arm was discontinued as the dose of 5.6 mg/kg of patritumab deruxtecan was selected following a risk-benefit analysis conducted from the phase 1 trial assessing the doses in a similar patient population. The primary endpoint of HERTHENA-Lung01 was ORR as assessed by BICR. Secondary endpoints included duration of response, PFS, disease control rate, and time to response – all assessed by both BICR and investigator assessment – as well as investigator-assessed ORR, OS, safety and tolerability. The data presented at WCLC is from the first arm and based on the fixed-dose (5.6 mg/kg) regimen. HERTHENA-Lung01 enrolled patients in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov. About EGFR-Mutated Non-Small Cell Lung Cancer Lung cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide.5 NSCLC accounts for approximately 85% of all lung cancers – 55% having distant spread at diagnosis – with EGFR mutations occurring in 14% to 38% of all NSCLC tumors worldwide.1,2,3 The introduction of targeted therapies has improved the treatment landscape for patients with EGFR-mutated locally advanced or metastatic NSCLC. Targeted therapy with EGFR TKIs offers higher response rates, PFS and potential OS advantage, compared to chemotherapy, with third generation EGFR TKIs demonstrating superior efficacy compared to earlier generation inhibitors.1 However, disease progression from resistance to EGFR TKIs inevitably occurs one to two years following initial treatment.6 After failure of EGFR TKI and platinum-based chemotherapy, currently available therapies offer limited efficacy.3,4 A recent real-world analysis of the treatment of patients in this setting showed that the median PFS in this setting is 3.3 months (95% CI: 2.8-4.4) and median OS is 8.6 months (95% CI: 7.4-9.8). An estimated real-world ORR of 14.1% (95% CI: 3.7%-33.1%) also has been observed.7,8 New treatment approaches are needed to help improve clinical outcomes in patients with EGFR-mutated NSCLC. About HER3 HER3 is a member of the EGFR family of receptor tyrosine kinases.9 It is estimated that about 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors express HER3 after prior EGFR TKI treatment.10,11 There is currently no HER3 directed therapy approved for the treatment of any cancer. About Patritumab Deruxtecan Patritumab deruxtecan (HER3-DXd) is an investigational HER3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is composed of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Patritumab deruxtecan was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in December 2021 for the treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies. Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other therapies in a global development program, which includes HERTHENA-Lung02, a phase 3 trial versus platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression on or after treatment with a third-generation EGFR TKI; a phase 1 trial in combination with osimertinib in EGFR-mutated locally advanced or metastatic NSCLC; and a phase 1 trial in previously treated patients with advanced NSCLC. A phase 1/2 trial in HER3 expressing metastatic breast cancer also has been completed. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Four additional Daiichi Sankyo DXd ADCs include patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, and DS-3939, a TA-MUC1 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit . Disclosure: Dr. Yu has a consulting relationship with Daiichi Sankyo. ______________________ References: 1 Economopoulou P, et al. Ann Transl Med. 2018; 6(8):138. 2 Chen R, et al. J Hematol Oncol. 2020; 13(1):58. 3 Zhang Y-L, et al. Oncotarget. 2016; 7(48):78985-78993. 4 Janne PA, et al. Cancer Discov. 2022; 12(1):74-89. 5 World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Accessed January 2023. 6 Janne PA, et al. N Engl J Med 2015; 372:1689-1699. 7 Patel JD, et al. AACR 2023. Poster 6754. 8 Patel JD, et al. IASLC 2023 WCLC. Abstract 2201. 9 Mishra R, et al. Oncol Rev. 2018; 12(355):45-62. 10 Scharpenseel H, et al. Scientific Reports. 2019; 9:7406. 11 Yonesaka K, et al. Clin Cancer Res. 2022; 15:28(2):390-403. View source version on businesswire.com: Contacts Global/US: Jennifer Brennan Daiichi Sankyo, Inc. jbrennan2@dsi.com +1 908 900 3183 (mobile) Japan: Koji Ogiwara Daiichi Sankyo Co., Ltd. ogiwara.koji.ay@daiichisankyo.co.jp +81 3 6225 1126 (office) Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp Source: Daiichi Sankyo View this news release online at:

临床结果临床1期临床2期突破性疗法临床3期

2023-08-22

·CPHI制药在线

研发 | HER3靶点距离成药再近一步：双抗、ADC、疫苗、PROTAC……

关注并星标CPHI制药在线七夕爱你不止朝朝夕夕HER3是HER家族中唯一缺乏或几乎没有酪氨酸激酶内在活性的成员，需要与其他受体HER1、HER2或HER4形成异二聚体发挥功能。研究者还发现，HER3经常与肿瘤细胞中其他受体酪氨酸激酶（RTK）共同表达并形成异二聚体，激活致癌信号通路，特别是PI3K/Akt、MAPK/ERK和JAK/STAT通路和Src激酶。目前，在多种肿瘤中都检测到了HER3表达，包括乳腺癌、卵巢癌、结肠癌、胃癌等，HER3的高表达与疾病进展以及不良预后相关。因此HER3成为肿瘤治疗的研发热点。处于研发中的HER3靶点治疗药物包括：单抗、双抗、HER3-ADC药物以及抗HER3肿瘤疫苗等。双抗由于HER3结合力低、激酶活性依赖于异源二聚体激活等，其成药难度较大，以往探索的HER3单抗单药或者联用疗法基本折戟，包括罗氏的RO5479599、第一三共的U3-1287在内的多款HER3单抗相继以失败告终。随着研发人员对HER3作用机制洞察更加深刻，以及生物技术的进步，双抗、ADC有望成为HER3靶点新的解决方案。 Merus：MCLA-128MCLA-128是Merus开发的一款HER2/HER3双特异性抗体，其构建采用了Merus的Biclonics双特异性抗体平台技术：利用共同轻链技术防止重链与轻链的错配，CH3结构域采用带不同电荷的氨基酸突变，防止重链和重链的错配。同时抗体的Fc端采取了ADCC增强的突变策略，以利用ADCC效应增加对肿瘤细胞的杀伤。在2022年的ASCO年会上，Merus公布了MCLA-128治疗NRG1融合肿瘤的II期临床数据。NRG1是EGF配体家族的一员，与ERBB家族受体酪氨酸激酶结合参与细胞的生长，增殖等。NRG1作为ERBB的激动剂或配体，与ERBBs结合后，形成二聚体复合物NRG1/ERBBs，激活信号通路。研究结果显示，71例可评估患者的客观缓解率为34%，其中针对非小细胞肺癌（NSCLC）患者的客观缓解率为35%。 ADC 与单抗相比，ADC的优势是通过诱导受体内吞和降解导致癌细胞死亡，不必完全依赖HER3诱导癌细胞死亡。因此，ADC药物或是HER3靶点最有希望成功的药物。第一三共：U3-1402（Patritumab Deruxtecan）U3-1402是第一三共继Enhertu 和 Dato-DXd 之后的第3款ADC药物，也是第一三共首个未与外部合作、独立开发和商业化的ADC新药。U3-1402的抗体部分为HER3 单抗 patritumab（U3-1287），通过linker共价偶联拓扑异构酶I抑制剂依喜替康（exatecan），每个抗体连接有8个依喜替康。通过与肿瘤细胞表面的HER3结合，U3-1402被内吞入细胞内释放出依喜替康，进而发挥细胞毒作用，杀灭肿瘤细胞。在今年9月初即将召开的2023世界肺癌大会（WCLC）上，第一三共将报告U3-1402的关键II期临床试验HERTHENA-Lung01的研究结果。这项II期临床试验中纳入既往接受过一种 EGFR-TKI 治疗和铂类化疗的晚期EGFR 突变NSCLC患者。结果显示，在 5.6 mg/kg 组共225例患者接受了U3-1402给药。截至 2022 年 11 月 21 日，中位试验持续时间为 13.1 个月（范围 9.0-21.6），中位治疗持续时间为 5.5 个月（范围 0.7-18.2）。BICR 评估的客观缓解率为28.4%，中位缓解持续时间为 6.0 个月，中位无进展生存期为5.5个月，初步评估的中位总生存期为11.9个月。既往接受过前线奥希替尼治疗的患者表现出了相似的临床获益，同时在不同 HER3 表达水平和多种不同 EGFR-TKI 耐药机制中都观察到了临床活性。百利天恒：BL-B01D1BL-B01D1是百利天恒自主研发的全球首创EGFR/HER3 双抗ADC药物。BL-B01D1于今年7月获FDA批准，开展用于治疗复发和难治性非小细胞肺癌的临床试验。在国内已开展的临床试验中，BL-B01D1在NSCLC中的临床表现疗效优异，展现了具备突破性疗效的有效性。疫苗 Ad-HER3-FL靶向HER3的疫苗也处于临床前研究中。Ad-HER3-FL是一种靶向HER3的疫苗，可刺激小鼠模型中HER3特异性T细胞和抗体的产生，这表明HER3可能是抗肿瘤疫苗的良好靶点。在同一项研究中，Ad-HER3-FL与抗PD-1单抗联合使用，与单独的疫苗相比，反应明显增强，但仍需要进一步的临床前和临床研究评估。 PROTAC 蛋白酶体降解已成为一种新的治疗手段，包括蛋白水解靶向嵌合体（PROTAC）。PROTAC可以靶向HER3并诱导靶点进入细胞降解。尽管针对HER3的PROTAC还没有报道，但是目前部分报道的单抗可以实现HER3的部分降解，如NG33，被证明可以诱导HER3降解并抑制HER2驱动的癌细胞的生长。HER3也可以被与HER2结合的交联形式的曲妥珠单抗也会降解。与其他EGFR家族成员不同，HER3单独过表达时并不致癌。但HER2/HER3异源二聚体在所有可能的EGFR家族二聚体中具有最高的转化能力。二聚体卓越的致癌能力使HER3在HER2介导的多种类型的癌症发生中发挥重要作用。HER3当前越来越受到关注。其有效性和安全性需要更多数据来验证，生物标记物的应用、获益人群的选择等问题也等待解答。HER3药物研发要走的路还很长。虽然靶向HER3的药物研发还有很多不确定性，但HER3距离成药无疑越来越近。主要参考资料： 1、Dolgin E. HER3-addicted tumors: how biotechs are closing in. Nat Biotechnol. 2022 Aug;40(8):1157-1159. doi: 10.1038/s41587-022-01425-9. PMID: 35945436. 2、Haikala HM, J?nne PA. Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Clin Cancer Res. 2021 Jul 1;27(13):3528-3539. doi: 10.1158/1078-0432.CCR-20-4465. Epub 2021 Feb 19. PMID: 33608318; PMCID: PMC8254743. 3、Heidi M. Haikalaand Pasi A. J€anne. Thirty Years of HER3: From Basic Biology to Therapeutic Interventions.AACR 2021. 4、Shi F, Telesco SE, Liu Y, RadhakrishnanR, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP andcatalyze autophosphorylation. Proc Natl Acad Sci U S A 2010;107:7692–7.智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

抗体药物偶联物ASCO会议临床结果疫苗蛋白降解靶向嵌合体

2023-03-02

·BioSpace

Prenetics Announces Formation of Scientific Advisory Board to Support New Business Strategy in Precision Oncology

LONDON and HONG KONG, March 02, 2023 (GLOBE NEWSWIRE) -- Prenetics Global Limited (NASDAQ: PRE), a leader in genomic and diagnostic testing, is proud to announce the formation of a new Prenetics Scientific Advisory Board (the ‘SAB’) to provide strategic input based on their scientific knowledge and clinical expertise to help guide the further development of Prenetics’ diagnostic cancer genomics platform. Prenetics has been at the forefront of genomic and diagnostic testing, providing a wide range of genetic testing services to individuals and healthcare professionals around the world. The SAB includes a diverse group of highly respected experts in oncology and genomics, each with unique expertise and backgrounds in the field of precision oncology. Members of the board include Prof. Tony Mok, Prof. Pasi Jänne, Prof. Pan-Chyr Yang, Dr. Hua-Chien Chen, Dr. Frank Ong, and Dr. Lawrence Tzang. “We are honoured to have these accomplished scientific thought-leaders join Prenetics’ SAB," said Danny Yeung, CEO and Co-Founder of Prenetics. "Their insights and experience will be an invaluable asset to fuel our innovative solutions in the field of precision oncology. We are particularly excited in the area of early detection for cancer and will share more details in the coming months.” “We are thrilled to have Prof. Mok chair our SAB,” Mr. Yeung continued, “Prof. Mok’s passion for innovation make him a great fit for Prenetics and look forward to working together to transform the way cancer is identified and treated. Prof. Mok’s research has already guided the development of breakthroughs for lung cancer treatment and he has been recognized globally for his impact on the field of precision oncology.” Prof. Mok added, “I am delighted to be joining Prenetics and to have the opportunity to work with such a dynamic and innovative team. Precision oncology is a rapidly evolving field, and I believe that Prenetics is well-positioned to make a significant impact in this area. I look forward to contributing my expertise to this important work.” Prenetics’ SAB appointees include: Prof. Tony S. K. Mok Prof. Mok will lead the SAB and currently serves as Chairman of the Department of Clinical Oncology of Chinese University of Hong Kong, is a non-executive director of AstraZeneca plc, and an independent director of HUTCHMED (China) Limited. His main research interest focuses on biomarker and molecular targeted therapy in lung cancer. Prof. Mok was the Principal Investigator and first author on the landmark IRESSA® Pan-Asia Study (IPASS), which was the first study that confirmed the application of precision medicine for advanced lung cancer. He has also led and co-led multiple studies including the FASTACT 2, IMPRESS, ARCHER 1050, ALEX and AURA 3. These projects address various aspects on management of EGFR mutation positive lung cancer, and have played a significant role in defining current practice. Prof. Mok has also engaged in clinical research on ALK positive lung cancer and immunotherapy. The series of clinical trials, led or co-led by Professor Mok, have defined precision medicine. His work has been adopted by multiple international guidelines including NCCN, AMP/IASLC/CAP, ASCO and ESMO. Prof. Pasi A. Jänne, MD, PhD Prof. Pasi Jänne is a globally renowned translational thoracic medical oncologist at the Dana Farber Cancer Institute and Professor of Medicine at Harvard Medical School. He is also the Director of the Lowe Center for Thoracic Oncology and the Director of the Belfer Center for Applied Cancer Science. Prof. Jänne's research combines laboratory-based study with translational research in clinical trial of novel therapeutic agents in patients with lung cancer. He has made seminal therapeutic discovery including co-discovery of EGFR mutations and has led the development of therapeutic strategies for patients with EGFR mutant lung cancer. Prof. Pasi Jänne's translational research work also led to the successful development of HER3-ADC in NSCLC and combination with Osimertinib to further enhance the potential efficacy of HER3-ADC. Prof. Jänne has received multiple awards for his work including from the AACR, ESMO and ASCO. Prof. Pan-Chyr Yang, PhD Prof. Yang is the former President of Taiwan University and has been a professor in the department of internal medicine at the College of Medicine for 27 years. He has also served as the Director of the Advisory Office for the Ministry of Education and as Dean for the College of Medicine at Taiwan University. Dr. Yang was honoured with the Joseph W. Cullen Prevention/Early Detection Award at the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer. Prof. Yang is a pioneer and leader in pulmonary ultrasound diagnostics and therapeutics that have revolutionized the management of pulmonary diseases which include lung cancer. He has led a research group to develop the method for detection and quantification circulating cancer cells in peripheral blood and to better predict the prognosis and response to treatment for lung cancer patients. He has led a research group to discover novel genes and pathways that are associated with lung cancer pathogenesis and progression. They identified specific gene expression and microRNA signatures that can assist to predict the treatment outcome and may be beneficial for personalized therapy of lung cancer patients. Dr. Hua-Chien Chen, PhD Dr. Hua Chien Chen is the Co-founder and the Chief Scientific Officer of ACT Genomics. He has more than 20 years of experience in cancer biology, genomics and drug discovery. Dr. Hua Chien Chen earned his PhD in Biochemistry from National Yang-Ming University in Taiwan and completed his postdoctoral training in Molecular Biology at Case Western Reserve University in the USA. In 1998, Dr Hua Chien Chen was an Assistant Investigator at the National Health Research Institute, where he worked on the discovery and development of molecular targets for new drugs. Dr. Chen then joined TaiGen Biotechnology as the Biology Director, where he oversaw the drug screening program. From 2006 to 2014, Dr. Chen took up a position as Associate Professor at Chang Gung University, where he established a multiplexed micro-RNA quantification platform for the Molecular Medicine Research Center. This platform was developed to identify non-invasive biomarkers for cancer and other diseases. Dr. Hua Chien Chen has extensive experience in the biotech industry, technology-based project evaluation and license negotiation. Dr. Chen is also an accomplished scientist and acknowledged expert in the fields of molecular biology, oncology and genomics. Dr. Frank S. Ong, MD Dr. Frank Ong, MD. Chief Medical Officer for Prenetics and Interim CEO for ACT Genomics is a seasoned industry-leading physician-scientist in Clinical Development (Certified Principal Investigator, Certified Clinical Research Professional, Medical Monitor) and Medical Affairs with clinical fellowship specialization in medical genetics and sub-specialization in clinical molecular genomics laboratory testing for hereditary oncology, common and rare hereditary adult and pediatric conditions, pharmacogenetics, carrier screening, and women's health. Prior to joining Prenetics as Group Chief Medical Officer, Dr. Ong was the Chief Medical Officer and Chief Scientific Officer of Everly Health and held previous leadership roles in Guardant Health, Illumina and Roche. Dr. Ong led the first FDA 510(k) cleared NGS-based assay and NGS platform in 2013 as well as the first at-home COVID test to obtain Emergency Use Authorization by the US FDA in 2020. Dr. Ong received his Medical Doctorate at the Keck School of Medicine of the University of Southern California in 2002, and completed his residency and fellowship at the University of California, Los Angeles and Cedars-Sinai Medical Center before serving on the faculty at Cedars-Sinai Medical Center. Dr. Lawrence T.C. Tzang, PhD Dr. Lawrence Tzang is the Co-Founder of Prenetics and has served as its Chief Scientific Officer and director since its founding in 2014. He has more than 20 years of experience in molecular diagnostics, genomics as well as laboratory automation. Dr. Tzang has been a registered Medical Laboratory Technologist I at the Board of Medical Laboratory Technologist since 2013, a founding member and ex-secretary at the Hong Kong Society for Behavioral and Neural Genetics in 2011-2022 and a fellow of the Hong Kong Society for Molecular Diagnostic Sciences since 2008. Dr. Tzang received his Ph.D. in Molecular Biology in 2003 and post-doctoral research fellowship at Department of Biology & Chemistry of the City University of Hong Kong from 2003 to 2009. Dr. Tzang used microarray technologies on gene expression profiling for cancer researches, including vimentin and clusterin gene expression in hepatocellular carcinoma metastasis and key role of a protein in hepatocarcinogenesis, as well as drug resistance in cervical carcinoma. Dr. Tzang has also developed a biochip based genotyping platform for human papillomavirus genotyping and prevalence analysis in cervical cancer. In addition, he also participated in deep proteome profiling of sera from never-smoked lung cancer patients. About Prenetics Prenetics is a leading genomics and precision oncology company dedicated to transforming patient care through advanced genomic and molecular technologies. Our new business focus is on precision oncology, specifically on early detection and treatment. We recently acquired ACT Genomics, the only Asia-based company to receive FDA clearance for a comprehensive genomics profiling test for solid tumors. ACT has also enabled us to expand our capabilities and offer comprehensive cancer solutions to patients worldwide. Our team of world-class scientists, healthcare experts, and technology innovators are committed to driving forward precision oncology to improve patient outcomes. At Prenetics, we believe that every patient deserves personalized, effective, and affordable cancer care, and we are dedicated to making that a reality. Prenetics is listed on NASDAQ with the ticker PRE. To learn more about Prenetics, visit About ACT Genomics ACT Genomics is an innovation-driven cancer solution provider with offices in Taipei, Hong Kong, Singapore, Tokyo, Bangkok and the United Kingdom. With its Next-Generation Sequencing (NGS) technology, CAP-accredited laboratories, experienced bioinformatics team, and proprietary AI algorithms, ACT Genomics provides optimal cancer treatment planning, immunotherapy evaluation, cancer relapse and drug resistance monitoring, as well as cancer risk assessment services to medical professionals. Its motto is “Turn Genomics into Action”. ACT Genomics is a group company of NASDAQ-listed Prenetics. To learn more about ACT Genomics, visit . Investor Relations Contact: Email: investors@prenetics.com ICR Westwicke: Caroline Corner +1 415 202 5678 Email: caroline.corner@westwicke.com Media contact: Strategic Public Relations Group Corinne Ho +852 2114 4911 Email: corinne.ho@sprg.com.hk Forward-Looking Statements In addition to historical information, this release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terminology such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “should,” “plan,” “expect,” “predict,” “potential,” or the negative of these terms or other similar expressions. These statements are based on estimates and forecasts and reflect the views, assumptions, expectations, and opinions of Prenetics and ACT Genomics. Any such estimates and assumptions, expectations, forecasts, views or opinions, whether or not identified in this press release, should be regarded as indicative, preliminary and for illustrative purposes only and should not be relied upon as being necessarily indicative of future results. These statements include, but are not limited to, statements by our management or the board regarding plans, objectives, strategic direction of Prenetics and ACT. Our expectations and beliefs regarding these matters may not materialize, and actual results in future periods are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Because of these uncertainties, you should not make any investment decisions based on our estimates or forward-looking statements. All information provided in this press release is as of the date of this press release. Prenetics does not undertake any obligation to update any forward-looking statement, whether as a result of new information, future developments, or otherwise, except as required under applicable law.

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100 项与 Anti-Her3 therapy(Band Therapeutics, LLC) 相关的药物交易

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