甾体类化合物ADC梳理:Ambrx/再生元/Abbvie/映恩
甾体类化合物
01
图1. Dexa-AbhEsel的构建及其对促炎基因IL-8的影响
02
丹麦Cytoguide公司--Anti-CD163-Dexa ADC
图2. ADC-Anti-CD163-Dexa的构建及其抗炎活性的评价
03
Merck联合Ambrx,基于新型焦磷酸二酯Linker开发系列ADC
接下作者将简要介绍该系列ADC的构建工作。
图5. 该类型ADC的细胞活性:α-hCD70(实验组)和α-RSV (对照组)
图6. 含有布地奈德载荷ADC的构建及其载荷释放机制
表1. 专利WO2015153401和WO2017062271内容的简单梳理
虽然anti-CD74-AXC496的活性没有Anti-CD74-flu449优秀,但作者更倾向于其产生的细胞特异性靶向递送,为降低该类型药物的毒副作用提供帮助。Anti-CD74-AXC496 (DAR=1.5)的活性低于Anti-CD74-flu449 (DAR=1.9)也有可能是其DAR较低的原因,后续若作者再提高其DAR值可能会消除这种活性较低的问题。
04
再生元:GC-ADCs 广泛的专利布局
再生元(Regeneron Pharmaceuticals, Inc.,)是一家美国生物技术公司,成立于1988年。该公司最初专注于神经营养因子及其再生能力而得名,后来又扩展到细胞因子、酪氨酸激酶受体等领域,其正在开发的商业化药物和候选产品旨在帮助患有眼疾、过敏性和炎症性疾病、癌症、心血管和代谢性疾病、疼痛、传染病和罕见疾病的患者。
Regeneron主要利用含有Q295、Q297反应位点的抗体构建GC-ADC,利用MTGase将含有氨基的底物(N3-PEG3-NH2)引入到目的抗体中,通过环张力驱动的叠氮炔基环加成反应(Strain-Promoted Azide−Alkyne Cycloaddition, SPAAC[11])进行位点特异性的偶联,获得DAR值为4的偶联物(图9),改善甾体类药物的口服生物利用度(F),降低肝脏首过效应,减少单独应用时所产生的副作用[4]。
图9. Regeneron GC-ADC的构建方法
专利WO2018089373引申出的GC-ADC (Anti-PRLR Ab-PEG3-Triazole-Suc-PEG4-vc-PABC-P3/P12)活性数据已发表在Journal of Medicinal Chemistry上[4]。利用该方法构建的GC-ADC (DAR≈4)与对照组(anti-Fel D1 Ab)相比,在抗原阳性细胞系中表现出有效的GR激活和超过其同类型Control GC-ADCs 100倍以上的选择性;此外,两种GC-ADCs (Payload为P3/P12)在混合抗原阳性和阴性细胞系中均表现出旁观者效应。
05
Abbvie: 专利WO2017210471与ABBV-154
相较于Regeneron而言,Abbvie在GC-ADC领域的专利-WO2017210471[13]布局更早,优先权日为2016年6月2日。在GC-ADC制备过程中,对偶联物中的硫代琥珀酰亚胺进行开环处理,使其稳定性增加,降低其因逆迈克尔加成反应所致的副反应[14]。作者对专利WO2017210471进行简单梳理,详细信息请参考专利内容(表3)。
图10. ABBV-3373结构及其临床数据、ABBV-154结构
基于上述ABBV-3373良好的临床试验结果,ABBV-154在其基础上做了“细微修改(slightly modified)”-C21位引入磷酸集团(图10右)。目前,ABBV-154已进行多项临床研究,具体内容如下表4所示。
06
映恩生物:DIMAC技术平台
国内药企映恩生物(DualityBio)开发出具有全球知识产权的DIMAC (Duality Immune Modulating Antibody Conjugate,双重免疫调节抗体偶联物)技术平台[23]。DIMAC技术平台主要针对自身免疫疾病而开发,例如系统性红斑狼疮(Systemic lupus erythematosus, SLE)。该技术平台构建GC-ADCs所选用Payload的活性强于传统的激素类小分子,具有长效的特点;可以降低给药频次低,提高患者的用药依从性;此外,其具有高度靶点特异性,可最大限度地减少甾体类药物的全身副作用[24]。
该平台技术专利-WO2022135332[25]于2022年6月30日公布,主要涉及一种甾体偶联物,作者将专利中的内容简要梳理如下表5所示。
基于上述DIMAC技术,以及对疾病生物学和转化能力的深刻理解,DualityBio有两款该类GC-ADC药物在研-DB2304[26]和DB2306[27],目前处于临床前研究阶段。此外,DualityBio DIMAC技术还涉及另一项专利WO2023040793[28],有兴趣的朋友可以和Abbive的专利-WO2017210471进行对比阅读。
免责声明:本文仅作信息交流之目的,文中观点不代表个人立场,亦不代表个人支持或反对文中观点。本文并非治疗方案推荐。如需获得治疗方案指导,请前往正规医院就诊。
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1. Fuentes-Antrás, J., et al., Antibody-drug conjugates: in search of partners of choice. Trends Cancer, 2023. 9(4): p. 339-354.2. Fu, Z., et al., Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther, 2022. 7(1): p. 93.3. Dragovich, P.S., Antibody-Drug Conjugates for Immunology. J Med Chem, 2022. 65(6): p. 4496-4499.4. Han, A., et al., Development of Novel Glucocorticoids for Use in Antibody-Drug Conjugates for the Treatment of Inflammatory Diseases. J Med Chem, 2021. 64(16): p. 11958-11971.5. Han, A., W. Olson, and A.J. Murphy, Preparation of novel steroids and their protein-conjugates for the target-specific delivery of glucocorticoids. 2018, Regeneron Pharmaceuticals, Inc.6. Han, A., Steroids and antibody-conjugates thereof useful for target-specific delivery of glucocorticoids to cells. 2019, Regeneron Pharmaceuticals, Inc.7. Han, A., Traceless linkers and protein-conjugates thereof. 2023, Regeneron Pharmaceuticals, Inc.8. Anami, Y. and K. Tsuchikama, Transglutaminase-Mediated Conjugations. Methods Mol Biol, 2020. 2078: p. 71-82.9. Dickgiesser, S., et al., Site-Specific Conjugation of Native Antibodies Using Engineered Microbial Transglutaminases. Bioconjug Chem, 2020. 31(4): p. 1070-1076.10. Han, A., Hydrophilic linkers for antibody drug conjugates. 2019, Regeneron Pharmaceuticals, Inc.11. Ramsubhag, R.R. and G.B. Dudley, Orthogonal dual-click diyne for CuAAC and/or SPAAC couplings. Organic & biomolecular chemistry, 2016. 14(22): p. 5028-5031.12. https://www.regeneron.com/pipeline-medicines/investigational-pipeline.13. McPherson, M.J., et al., Preparation of glucocorticoid receptor agonist and immunoconjugates thereof. 2017, AbbVie Inc.14. Huang, W., et al., Maleimide-thiol adducts stabilized through stretching. Nat Chem, 2019. 11(4): p. 310-319.15. Lu, X., et al., Efficacy and Safety of Adalimumab Biosimilars: Current Critical Clinical Data in Rheumatoid Arthritis. Front Immunol, 2021. 12: p. 638444.16. Hobson, A.D., et al., Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate. J Med Chem, 2022. 65(23): p. 15893-15934.17. Stoffel, B., et al., POS0365 anti-TNF glucocorticoid receptor modulator antibody drug conjugate for the treatment of autoimmune diseases. 2021, BMJ Publishing Group Ltd.18. D'Cunha, R., et al. ABBV-3373-A NOVEL IMMUNOLOGY ANTIBODY DRUG CONJUGATE: RESULTS FROM A FIRST-IN-HUMAN SINGLE ASCENDING DOSE STUDY IN HEALTHY SUBJECTS TO SUPPORT DOSE SELECTION FOR THE PROOF-OF-CONCEPT STUDY IN RHEUMATOID ARTHRITIS PATIENTS. in Clinical Pharmacology & Therapeutics. 2021. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.19. Buttgereit, F., et al., Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial. Arthritis Rheumatol, 2023. 75(6): p. 879-889.20. https://www.pharmaceutical-technology.com/data-insights/abbv-154-abbvie-polymyalgia-rheumatica-pmr-likelihood-of-approval/.21. https://endpts.com/abbvie-axes-two-candidates-as-company-revenue-drops-nearly-10/.22. https://www.abbvie.com/science/pipeline.html.23. https://www.dualitybiologics.com/approach.html?md=2.24. https://www.dualitybiologics.com/approach.html.25. Zhang, Y., et al., Steroid conjugate. 2022, Duality Biologics (Suzhou) Co., Ltd.26. Li, X., et al. DB-2304, a Novel anti-BDCA2 Monoclonal Antibody Drug Conjugate, Displayed Great Potency in Suppression of pDC Functions. in ARTHRITIS & RHEUMATOLOGY. 2022. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.27. Li, X., et al. DB-2306, a Novel Anti-TNF alpha Monoclonal Antibody Drug Conjugate, Is a Promising Novel Therapeutic Approach for Autoimmune Disease. in ARTHRITIS & RHEUMATOLOGY. 2022. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.28. Zhang, Y., et al., Anti-inflammatory compound and use thereof. 2023, Duality Biologics (Suzhou) Co., Ltd.
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