抗体医薬品評価サービス

前臨床から臨床への橋渡し：

抗体医薬品の半減期の迅速な比較を可能とするプラットフォーム

FcRnヒト化マウスモデルを用いることで、抗体医薬品やその他Fc領域ベースの医薬品の生体内での安定性を評価することが可能です。これは、マウスFcRnを欠損し、異なるレベルでヒトFcRnを発現しているユニークなプラットフォームであり、ジャクソンラボラトリーのDr. Derry Roopenianによって開発されました。これらのマウスは、特に以下の点で優れています。

生体内での抗体の安定性に関して、臨床予測に有用なデータを迅速に得られる点
非ヒト霊長類にとって代わる効果的かつ実証された代替手段である点
Fc領域ベースの治療候補の前臨床薬物動態（PK）解析ができる点
少量の分子を用いて試験可能なため、費用効果が高い点
免疫腫瘍学や自己免疫疾患の研究などで使用される、あらゆる種類のFc領域－アルブミン結合体、またはアルブミンに結合する治療薬の検査ができる点

薬物動態の前臨床試験におけるモデルと臨床との相関性

Model	Cost	Correlation with Human Data
In Vitro	Low	Low
Standard mice	Moderate	Low
Humanized FcRn mice	Moderate	Very good
Non-human primates	High	Very good

代表的なFcRnヒト化マウス系統

B6.Cg-Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) マウスは、マウスFcRn遺伝子のヌル変異を持ち、ヒトFcRnを内因性プロモーター下で発現するトランスジーン（hTg32）を持っています。このマウス系統ではヒトIgGが最もよく保護されるため、長い半減期データが必要な場合に最適なモデルです。

B6.Cg-Fcgrt^tm1Dcr Tg(CAG-FCGRT)276Dcr/DcrJ (004919) マウスは、マウスFcRn遺伝子のヌル変異を持ち、ヒトFcRnを発現するトランスジーン（hTg276）を持っています。ヒトFcRnトランスジーンを半数持つマウスは、体内での抗体持続性の微妙な違いを検出するのに最適です。

B6.Cg-Fcgrt^tm1Dcr Prkdc^scid Tg(FCGRT)32Dcr/DcrJ (018441) マウスは、hTg32トランスジーンを発現する免疫不全マウスです。これらのマウス系統では、ヒトIgGがヒト生体内でおきているのと同様、最もよく保護されます。潜在的に免疫原性があるか、もしくは異種移植に使用されるFc領域ベースの医薬品を用いた治療を評価するのに役立ちます。

B6.Cg-Alb^em12Mvw Fcgrt^tm1Dcr Tg(FCGRT)32Dcr/MvwJ (025201) アルブミンノックアウトhTg32マウスは、アルブミン結合体またはアルブミンによって運搬される医薬品の薬物動態の特性化に有効な、ヒトを模倣したモデルです。

Model	Endogenous promoter	Longest half-life	Can see subtle differences in PK values	Immuno-deficient	Albumin PK
FcRn Tg32 ( 014565 )	Yes	Yes	No	No	No
FcRn Tg276 ( 004919 )	No	No	Yes	No	No
Tg32 Scid ( 018441 )	Yes	Yes	No	Yes	No
Tg276 Scid* ( 021146 )	No	No	Yes	Yes	No
Tg276 Rag1* ( 016919 )	No	No	Yes	Yes	No
Tg32 Alb KO ( 025201 )	Yes	Yes	No	No	Yes

Avery LB, Wang M, Kavosi MS, Joyce A, Kurz JC, Fan YY, Dowty ME, Zhang M, Zhang Y, Cheng A, Hua F, Jones HM, Neubert H, Polzer RJ, O'Hara DM. 2016. Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. MAbs. 8(6):1064-78. PMID: 27232760

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

Haraya K, Tachibana T, Iwayanagi Y, Maeda A, Ozeki K, Nezu J, Ishigai M, Igawa T. 2016. PK/PD analysis of a novel pH-dependent antigen-binding antibody using a dynamic antibody-antigen binding model. Drug Metab Pharmacokinet. 31(2):123-32. PMID: 26944099

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

Haraya K; Tachibana T; Nanami M; Ishigai M. 2014. Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody. Xenobiotica. 44(12):1127-34. PMID: 25030041

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

Gehlsen K; Gong R; Bramhill D; Wiersma D; Kirkpatrick S; Wang Y; Feng Y; Dimitrov DS. 2012. Pharmacokinetics of engineered human monomeric and dimeric CH2 domains. MAbs. 4(4):466-74. PMID: 22699277

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

Christianson GJ; Sun VZ; Akilesh S; Pesavento E; Proetzel G; Roopenian DC. 2012. Monoclonal antibodies directed against human FcRn and their applications. MAbs. 4(2):208-16. PMID: 22453095

Stein C; Kling L; Proetzel G; Roopenian DC; de Angelis MH; Wolf E; Rathkolb B. 2012. Clinical chemistry of human FcRn transgenic mice. Mamm Genome. 23(3-4):259-69. PMID: 22193411

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

Ober RJ; Radu CG; Ghetie V; Ward ES. 2001. Differences in promiscuity for antibody-FcRn interactions across species: Implications for therapeutic antibodies. Int. Immunol 13(12):1551-9. PubMed: 117171962015 May;16(3):165-72. PMID: 25838158

関連資料

前臨床から臨床への橋渡し：

抗体医薬品の半減期の迅速な比較を可能とするプラットフォーム

薬物動態の前臨床試験におけるモデルと臨床との相関性

代表的なFcRnヒト化マウス系統

FcRn Humanized Mouse Models

PK試験のデザイン例

参考文献