IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab-pharmacokinetic modeling to optimize therapeutic index

Abstract

Purpose: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases.

Methods: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound "harmful" antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)].

Results: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%.

Conclusion: The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation.

Clinical trial registration: ClinicalTrials.gov , NCT00089245.

Keywords: 131I-omburtamab; Cerebrospinal fluid; Neuroblastoma; Pharmacokinetics; Radioimmunotherapy.

Figures

Fig. 1

Flow diagram of the two-compartment CSF model. Reprinted by permission from “Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid” by He et al., 2011., Eur J Nucl Med Mol Imaging, 38(2):334–42 [11].

Fig. 2

B7-H3 antigen density, NR, on human tumor cell lines (neuroblastoma (NB) or non-neuroblastoma) cultured in RPMI 1640 with 10% fetal bovine serum at 37C in 5% CO2. 8H9 was labeled with Alexa Fluor® 488 according to manufacturer’s instructions (Invitrogen, Catalog number A10235). B7-H3 quantitation was done using Quantum™ Simply Cellular® anti-Mouse beads (Bangs Laboratories, Catalog Code 815). A) By cell line B) Histogram (logarithmic scale).

Fig. 3

Predicted immunoreactivity effects on therapeutic index (and implicitly AUC[CIAR(t)]), relative to the current 69% immunoreactivity, for A) 74MBq (2mCi) and B) 1850MBq (50mCi) doses. Fixed-intercept linear regression is shown to illustrate concavity at high doses.

Fig. 4

Predicted effects of dose on therapeutic effectiveness, AUC[CIAR(t)], and collateral radiation, AUC[CIA(t)], (left vertical axis) and either A) therapeutic index (TI) or B) TI×AUC[CIAR(t)], relative to a reference point of a 1850MBq (50mCi) dose (right vertical axis). The figure uses R0=1.1937×1013 antigens/mL as this made AUC[CIAR(t)] and AUC[CIA(t)] fit concisely in one plot, but the trends are very similar regardless of R0. In Panel B, this changed the peak to 1508MBq (40.75mCi) from 1495MBq (40.41mCi).

Fig. 5

Predicted percentage improvement over single injection of A) therapeutic effectiveness, AUC[CIAR(t)], B) therapeutic index (TI), and C) TI×AUC[CIAR(t)] caused by various dose fractionation schemes with a constant total dose of 1850MBq (50mCi).

Fig. 6

Predicted receptor saturation over time at different doses (R0 = 1.1937×1012 ant/mL). See Supplemental Figure 6 for further details.

Fig. 7

A) Predicted effect of clearance (equal to CSF production or CSF flow rate) on therapeutic effectiveness and therapeutic index (TI). B) Predicted clearance effects mediated by unbinding component, k−AR, of KD. TI values are relative to dose=1850MBq (50mCi), k−AR=1.65×10−4, and CL=20mL/hr. TI at k−AR=0 continues linearly outside of figure bounds.

Fig. 8

Predicted effect on therapeutic effectiveness and therapeutic index (TI) by A) ventricular volume (total volume fixed) and B) total volume (compartment volumes proportional). TI values are relative to 30mL ventricular volume, 140mL total volume, and 1850MBq (50mCi) dose.