Therapeutic Antibody Evaluation Services

The JAX Therapeutic Antibody Evaluation Services rely on a unique humanized mouse collection. Using our humanized FcRn models we deliver accurate data to get your therapeutic candidate into the clinic—and ultimately in the hands of physician and patients—faster.

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From preclinical to clinical: get relevant translational and fast half-life comparison data

We evaluate the in vivo stability of therapeutic antibodies and other Fc-based biologics using our unique platform consisting of humanized mouse models that are deficient in murine FcRn and express human FcRn at different levels. Developed by JAX professor Derry Roopenian, Ph.D., these mice allow for
  • generation of faster, predicative clinically-relevant data for antibody stability,
  • an effective and proven alternative to non-human primates,
  • preclinical pharmacokinetic (PK) analysis of Fc-domain based therapeutic candidates,
  • cost effectiveness, since they require only small quantities of a given molecule,
  • testing of any kind of Fc-domain albumin-conjugate, or therapeutic carried by albumin used in immuno-oncology and autoimmune research, among others

Clinical Relevancy of Preclinical Models for Pharmacokinetics

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

The Humanized Mouse Platform: Description of the Most Used Models

B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) mice have a null mutation for the mouse gene and a transgene expressing the human FcRn under the endogenous promoter (hTg32). These mice have the highest, most human-like protection of humanized IgG and are the best model for use when maximum half-life data is required. 

B6.Cg-Fcgrttm1Dcr Tg(CAG-FCGRT)276Dcr/DcrJ (004919) mice carry a null mutation for the mouse gene and a transgene expressing human FcRn. Mice hemizygous for the human FcRn transgene (hTg276) are best suited to detect subtle differences in antibody persistence in vivo.

B6.Cg-Fcgrttm1Dcr Prkdcscid Tg(FCGRT)32Dcr/DcrJ (018441) mice express the hTg32 transgene and are immunodeficient. These mice have the highest, most human-like protection of humanized IgG and are useful in evaluating Fc-domain based therapeutics that are potentially immunogenic or involve xenografts.

B6.Cg-Albem12Mvw  Fcgrttm1Dcr Tg(FCGRT)32Dcr/MvwJ (025201) albumin knockout hTg32 mice are an effective, human-like model for characterization of the pharmacokinetics of albumin-conjugates, or therapeutics carried by albumin.

FcRn Humanized Mouse Models

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

*Only available via cryorecovery

Example Studies

Example Pharmacokinetic study design

Note: All studies are designed to client specifications
  • A standard study uses 6 B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) mice.
  • Test articles and a vehicle control are administered via IV.
  • Blood samples are collected 1, 2, 6, 10, 14, 18, 22, and 26 days after test article administration.
  • The concentration of the test article is quantified by ELISA and PK Solutions software is used to calculate the pharmacokinetic data.

 Example Pharmacodynamic study design

 Note: All studies are designed to client specifications

  • A standard study uses 6 B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (014565) mice.
  • Human IgG is administered via IV injection and blood collected 24 hours later.
  • Test articles and a vehicle control are administered via IV 1 hour after the blood collection.
  • Blood samples are collected at 32, 48, 56, 72, 96, 120, and 144 hours.
  • The concentration of the human IgG or albumin can be quantified by ELISA and PK Solutions software is used to calculate the pharmacodynamic data.

References

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