Managing Director NewGround Pharmaceutical Consulting LLC Foster City, California, United States
Objective: Immunoglobulin M (IgM) antibodies have either 10 (pentamer) or 12 (hexamer) antigen binding domains and this avidity renders them highly efficient at binding antigens present at low levels. Recently several engineered IgM antibodies have been explored as therapeutics for various diseases in clinical trials. However, unlike IgG, IgM is not subjected to FcRn-mediated recycling and large size of IgM may limit its tissue distribution. Therefore, there is great interest to better understand disposition of IgM in optimizing efficacy and minimizing toxicity. To our best knowledge, there is no physiological-based pharmacokinetic (PBPK) model for quantifying disposition of IgM in animals and human subjects. Therefore, this study aims to develop first whole-body two-pore PBPK model of IgM in mice.
Method: PK data of 131I-labelled anti-stage-specific embryonic antigen-1 (SSEA-1) IgM in blood, liver, spleen, kidneys, muscle, lung, heart, bone, thymus, and brain in BALB/c mice was used for model development. PK data of 131I-labelled human IgM 16.88 in blood, liver, and muscle of nude mice bearing ovarian cancer cells NIH:OVCAR-3 was used for model validation. PBPK models developed in this study consisted of 3 biological systems: blood, organs, and lymph nodes. In each organ, three spaces were defined: vascular, endothelial, and interstitial space. IgM moved from vascular and/or interstitial space to endothelial space by fluid-phase endocytosis. Due to large molecular weight (> 900 kDa), two-pore model suggested that only convection of small pores for spleen/liver and large pores for all organs plays an important role in transcapillary transport of IgM from vascular to interstitial space. All physiological and drug-specific parameters were fixed to reported values from literature except endothelial pinocytosis rate (KUP) and modulation factor for transcapillary flow (MT) which were estimated from model fitting. Performances of PBPK models in describing PK of 131I-Anti-SSEA-1 IgM were examined based on visual inspection of fitted curves and coefficient of variation (%CV) of fitted parameters. Developed model was then validated using PK data of 131I-labelled human IgM 16.88.
Result: Visual inspection of model prediction showed that developed PBPK models were able to describe PK of 131I-Anti-SSEA-1 IgM in different organs of BALB/c mice. Estimated KUP and MT for Anti-SSEA-1 IgM were 0.0786/h (%CV=4.6%) and 0.411 (%CV=22.5%), respectively. Validation of PBPK model to PK data of 131I-labelled human IgM 16.88 was successful based on acceptable visual inspection of fitted curves and %CV of estimated KUP (%CV=13.1%) and MT (%CV=22.8%).
Conclusion: To our best knowledge, this is the first reported whole-body two-pore PBPK model that was successfully used to describe disposition of IgM in mice. This developed PBPK model can increase our understanding of distribution and elimination of IgM.
Citations:
References: [1] Ballou B, Reiland JM, Levine G, et al. J Surg Oncol, 1986. 31(1):1-12. [2] Haisma HJ, Kessel MA, Muijen Mv, et al. Br J Cancer Suppl, 1990. 10:40-3. [3] Niederalt C, Kuepfer L, Solodenko J, et al. J Pharmacokinet Pharmacodyn. 2018; 45(2): 235–257. [4] Hardiansyah D, Ng CM. MAbs 2018;10(7):1144-1156
