治疗性抗体评估服务

AX 治疗性抗体评估服务利用了独特的人源化小鼠。我们的人源化 FcRn 模型可以提供准确的数据，缩短候选治疗药物进入临床所需的时间，并最终将药物交给医生和患者本人。

从临床前到临床：获得相关的转化和快速的半衰期比较数据

我们借助自身独有的平台（由缺乏鼠 FcRn 并以不同水平表达人 FcRn 的人源化小鼠模型组成）评估治疗性抗体和其他基于 Fc 的生物制剂的体内稳定性。这些小鼠由 来自JAX 的Derry Roopenian教授构建，具有以下优势

• 产生更快、可预测的与临床相关的抗体稳定性数据，
• 一种有效且已被证实的非人灵长类动物替代，
• 基于 Fc 结构域的候选治疗药物的临床前药代动力学 (PK) 分析，
• 性价比高，只需要少量的特定分子，
• 测试用于免疫肿瘤学和自身免疫研究的各种 Fc 结构域白蛋白融合药物或采用了白蛋白的治疗方法等

 

临床前模型的药代动力学临床相关性

模型	成本	与人体数据的相关性
体外	低	低
普通小鼠	中度	低
人源化 FcRn 小鼠	中度	极高
非人灵长类动物	高	极高

 

人源化小鼠平台： 常用模型

B6.Cg-Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠具有靶向突变导致的基因缺失，且存在一个在内源性启动子 (hTg32) 驱动下表达的人 FcRn 的转基因。这些小鼠对人源化 IgG 抗体具有高效和类似人类的保护作用，是在需要最大半衰期数据时使用的最佳模型。

 

B6.Cg-Fcgrt^tm1Dcr Tg(CAG-FCGRT)276Dcr/DcrJ (004919) 小鼠具有靶向突变导致的基因缺失和表达人 FcRn 的转基因。 人 FcRn 转基因 (hTg276) 的半合子小鼠适合检测体内抗体持久性的细微差异。

 

B6.Cg-Fcgrt^tm1Dcr Prkdc^scid Tg(FCGRT)32Dcr/DcrJ (018441) 小鼠表达 hTg32 转基因，同时免疫缺陷。这些小鼠对人源化 IgG 具有高效和类似人类的保护作用，可用于评价具有潜在免疫原性或涉及异种移植物的基于 Fc 结构域的治疗药物。

 

B6.Cg-Alb^em12Mvw  Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/MvwJ (025201) 白蛋白敲除 hTg32 小鼠是一种有效的类人模型，可用于表征白蛋白融合药物或基于白蛋白的疗法的药代动力学。

 

 

模型	内源性启动子	最长的半衰期	评价 PK 值的细微差异	免疫缺陷	白蛋白 PK
FcRn Tg32 (014565)	是	是	否	否	否
FcRn Tg276 (004919)	否	否	是	否	否
Tg32 Scid (018441)	是	是	否	是	否
Tg276 Scid* (021146)	否	否	是	是	否
Tg276 Rag1* (016919)	否	否	是	是	否
Tg32 Alb KO (025201)	是	是	否	否	是

*需冷冻复苏

 

 

 

药代动力学研究设计示例

注： 所有研究均按照客户要求设计

• 一项使用了 6 只 B6.Cg-Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠的标准研究。
• 实验药物及空白对照均通过 IV（静脉注射）给药。
• 实验药物经 IV 给药后 1、2、6、10、14、18、22 和 26 天采集血样。
• 通过 ELISA 定量分析实验药物的浓度，并使用 PK Solutions 软件计算药代动力学数据。

 

 药效学研究设计示例

 注： 所有研究均按照客户要求设计

• 一项使用了 6 只 B6.Cg-Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) 小鼠的标准研究。
• 通过 IV 给予小鼠人 IgG，24 小时后采集血样。
• 采血后 1 小时，通过 IV 给予实验药物和空白对照。
• 32、48、56、72、96、120 和 144 小时后采集血样。
• 通过 ELISA 定量分析人 IgG 或白蛋白的浓度，并使用 PK Solutions 软件计算药效学数据。

 

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Fan YY, Avery LB, Wang M, O'Hara DM, Leung S, Neubert H. 2016. Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice. MAbs. 8(5):848-53. PMID: 27104806

 

Hamblett KJ, Le T, Rock BM, Rock DA, Siu S, Huard JN, Conner KP, Milburn RR, O'Neill JW, Tometsko ME, Fanslow WC. 2016. Altering Antibody-Drug Conjugate Binding to the Neonatal Fc Receptor Impacts Efficacy and Tolerability. Mol Pharm. 13(7):2387-96. PMID: 27248573

 

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Low BE, Wiles MV. 2016. A Humanized Mouse Model to Study Human Albumin and Albumin Conjugates Pharmacokinetics. Methods Mol Biol. 1438:115-22. PMID: 27150087

 

Roopenian DC, Christianson GJ, Proetzel G, Sproule TJ. 2016. Human FcRn Transgenic Mice for Pharmacokinetic Evaluation of Therapeutic Antibodies. Methods Mol Biol. 1438:103-14. PMID: 27150086

 

Abdiche YN; Yeung YA; Chaparro-Riggers J; Barman I; Strop P; Chin SM; Pham A; Bolton G; McDonough D; Lindquist K; Pons J; Rajpal A. 2015. The neonatal Fc receptor (FcRn) binds independently to both sites of the IgG homodimer with identical affinity. MAbs. 7(2):331-43. PMID: 25658443

 

Roopenian DC; Low BE; Christianson GJ; Proetzel G; Sproule TJ; Wiles MV. 2015. Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs. MAbs. 7(2):344-51. PMID: 25654695

 

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Powner MB; McKenzie JA; Christianson GJ; Roopenian DC; Fruttiger M. 2014. Expression of neonatal Fc receptor in the eye. Invest Ophthalmol Vis Sci. 55(3):1607-15. PMID: 24550358

 

Monnet C; Jorieux S; Souyris N; Zaki O; Jacquet A; Fournier N; Crozet F; de Romeuf C; Bouayadi K; Urbain R; Behrens CK; Mondon P; Fontayne A. 2014. Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody. MAbs. 6(2):422-36. PMID: 24492301

 

Proetzel G; Wiles MV; Roopenian DC. 2014. Genetically engineered humanized mouse models for preclinical antibody studies. BioDrugs. 28(2):171-80. PMID: 24150980

 

Proetzel G; Roopenian DC. 2014. Humanized FcRn mouse models for evaluating pharmacokinetics of human IgG antibodies. Methods. 65(1):148-53. PMID: 23867339

 

Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F, Higuchi Y, Ishii S, Tamba S, Hironiwa N, Nagano K, Wakabayashi T, Tsunoda H, Hattori K. 2013. Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS One. 8(5):e63236. PMID: 23667591

 

Tam SH; McCarthy SG; Brosnan K; Goldberg KM; Scallon BJ. 2013. Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities. MAbs. 5(3):397-405. PMID: 23549129

 

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Andersen JT; Foss S; Kenanova VE; Olafsen T; Leikfoss IS; Roopenian DC; Wu AM; Sandlie I. 2012. Anti-carcinoembryonic antigen single-chain variable fragment antibody variants bind mouse and human neonatal Fc receptor with different affinities that reveal distinct cross-species differences in serum half-life. J Biol Chem. 287(27):22927-37. PMID: 22570488

 

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Liu L; Stadheim A; Hamuro L; Pittman T; Wang W; Zha D; Hochman J; Prueksaritanont T. 2011. Pharmacokinetics of IgG1 monoclonal antibodies produced in humanized Pichia pastoris with specific glycoforms: a comparative study with CHO produced materials. Biologicals. 39(4):205-10. PMID: 21723741

 

Wang W; Vlasak J; Li Y; Pristatsky P; Fang Y; Pittman T; Roman J; Wang Y; Prueksaritanont T; Ionescu R. 2011. Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. Mol Immunol. 48(6-7):860-6. PMID: 21256596

 

Roopenian DC; Christianson GJ; Sproule TJ. 2010. Human FcRn transgenic mice for pharmacokinetic evaluation of therapeutic antibodies. Methods Mol Biol 602:93-104. PMID: 20012394 

 

Zalevsky J; Chamberlain AK; Horton HM; Karki S; Leung IW; Sproule TJ; Lazar GA; Roopenian DC; Desjarlais JR. 2010. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 28(2):157-9. PMID: 20081867

 

Petkova SB; Akilesh S; Sproule TJ; Christianson GJ; Al Khabbaz H; Brown AC; Presta LG; Meng YG; Roopenian DC. 2006. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18(12):1759-69. PMID: 17077181 

 

Chaudhury C; Mehnaz S; Robinson JM; Hayton WL; Pearl DK; Roopenian DC; Anderson CL. 2003. The major histocompatibility complexrelated Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 197(3):315-22. PMID: 12566415 

 

Liu XY; Pop LM; Roopenian DC; Ghetie V; Vitetta ES; Smallshaw JE. 2006. Generation and characterization of a novel tetravalent anti-CD22 antibody with improved antitumor activity and pharmacokinetics. Int Immunopharmacol. 6(5):791-9. PMID: 16546710

 

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