Iodine-131-tositumomab

Example 7

FIGS. 7A and 7B show that CUX-0404A inhibits CK1epsilon but with less potency than TGR-1202. Inhibition of CK1epsilon was tested utilizing a radioisotope filtration binding assay. Compounds were tested in 10-dose IC50 mode with 3-fold serial dilution starting at 100 μM (FIG. 7A). Control Compound, D4476, was tested in 10-dose IC50 mode with 3-fold serial dilution starting at 20 μM (FIG. 7B). Reactions were carried out at 10 μM ATP. CUX-0404A had an IC50 of 3.21 μM. TGR-1202 had an IC50 of 0.62 μM.

As will be apparent to one of ordinary skill in the art from a reading of this disclosure, further embodiments of the present invention can be presented in forms other than those specifically disclosed above. The particular embodiments described above are, therefore, to be considered as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are considered to be within the scope of this invention. Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and rearranged in various ways within the scope and spirit of the invention. The scope of the invention is as set forth in the appended claims and equivalents thereof, rather than being limited to the examples contained in the foregoing description.

Example 2

Zirconium-89 (⁸⁹Zr) is a relatively-lived positron-emitting radioisotope (physical half-life: 3.27 days) which has been successfully used to radiolabel and image positron emission tomography (PET) human tumor xenografts in mice using tumor-targeted antibodies, several of which are now in clinical trial, for example, ⁸⁹Zr-trastuzumab, ⁸⁹Zr-huJ591, ⁸⁹Zr-MSTP2109A, ⁸⁹Zr-Df-IAB2M, ⁸⁹Zr-cmAb-U36, ⁸⁹Zr-ibritumomab tiuxetan, ⁸⁹Zr-bevacizumab, and ⁸⁹Zr-rituximab. By serial PET imaging, the tumor and normal-tissue kinetics (e.g., time-activity data) of such ⁸⁹Zr-labeled antibodies can be non-invasively measured in individual patients. The non-linear compartmental model of antibody kinetics described in herein is completely general and can be fit to the ⁸⁹Zr-labeled antibody kinetics measured in specific patients.

As described herein, the fitted patient-specific model can be used for computer-based simulations of the antibody kinetics as a function of the antibody dose (in milligrams or millimoles, for example) and an optimum antibody dose determined. The optimum dose comprises the dose that yields the highest tumor-to-normal tissue ratio of the antibody concentration integrated over time. The patient can then be administered his or her model-defined optimum antibody dose with the antibody now carrying a therapeutic payload such as anti-cancer drug or a therapeutic radionuclide.

In certain embodiments, anti-cancer drugs include any of the more than 200 cancer drugs identified by the NIH at http://www.cancer.gov/about-cancer/treatment/drugs, the contents of which are hereby incorporated by reference in its entirety. Table 2 shows exemplary drugs identified by the NIH.

In certain embodiments, anti-cancer drugs used herein are classes of drugs including, but not limited to the following: calicheamicin, doxirubicin, dolstatin/auristatin, maytansine, emtansine, ravtansine, alpha amanitin, pyrolobenzodiazapine, tubulysins, dasatinib and other pathway inhibitors, and bevatuzimab.

In certain embodiments, anti-cancer drugs used herein are classes of drugs targeting human epidermal growth factor receptor 3 (HER3), such as GSK2849330. HER3 expression is seen across a wide variety of solid malignancies and is associated with poor prognosis. Up-regulation of HER3 expression and activity is also associated with resistance to multiple pathway inhibitors. In certain embodiments, an anti-cancer drug used herein includes GSK2849330, a mAb targeting HER3. In certain embodiments, the disclosed non-linear model characterizes the biodistribution and dose-receptor occupancy relationship of GSK2849330 in subjects with advanced HER3 expressing solid tumors via PET imaging. Such a characterization is conducted in two parts. Part 1 includes the imaging phase where each subject will receive two doses of GSK2849330 containing both ⁸⁹Zr labelled GSK2849330 and unlabeled GSK2849330. The amount of unlabeled GSK2849330 present in each dose is varied to explore the effect on target mediated uptake of ⁸⁹Zr into HER3 expressing tissues and tumors. Subjects then proceed to the continuation phase (or Part 2) for continued treatment with unlabeled GSK2849330.

In certain embodiments, anti-cancer drugs used herein are classes of drugs targeting human carcinoembryonic antigen (e.g., CEA, CD66e) on cells (e.g., tumor cells, cluster of differentiation 3 (CD3) positive T-cells), such as AMG 211. AMG 211 is a bispecific single-chain antibody construct of the bispecific T-cell engager class and is a targeted drug in the treatment of relapsed/refractory gastrointestinal adenocarcinoma, or other CEA expressing tumors.

A well-known challenge in current drug development using targeted therapies is the high level of heterogeneity of target expression that is present in specific tumor types. The disclosed non-linear compartmental model, including radiolabeling of antibodies, provides a methodology to overcome this challenge.

In FIG. 6, the biodistributions (or the percent of the administered activity per gram of tissue, % IA/g) at 244 hours post-administration of ⁸⁹Zr-DFO-hu11B6 and ²²⁵Ac-DOTA-hu11B6 antibody targeting breast cancer in mice bearing human BT474 breast tumor xenografts are compared and shown, within experimental error, to be identical (lg-int: large intestine; sm-int: small intestine). Notably, even with the administration of hormones, progesterone (“Prog.”) or estrogen (“Estro.”), which impact the levels of expression of the hu11B6 target antigen, the biodistributions of these two radiolabeled forms of the hu11B6 antibody (Diaprost, Inc.; Lund, Sweden) remained identical. Thus, (1) the biodistribution, including tumor uptake, of the therapeutic ²²⁵Ac-DOTA-hu11B6 antibody can be accurately measured prior to therapy with the diagnostic ⁸⁹Zr-DFO-hu11B6 antibody and (2) the model-predicted optimum dose of hu11B6 antibody, based on the measured kinetics of ⁸⁹Zr-DFO-hu11B6 antibody, is the same for both ⁸⁹Zr-DFO-hu11B6 and ²²⁵Ac-DOTA-hu11B6 antibody. While the biodistribution data shown in FIG. 6 are for single time point, 244 hours, post administration of radiolabeled hu11B6, as with all systemically administered materials, can change the biodistribution profiles with time and thus require kinetic (e.g., time-varying) analysis (such as that provided by the non-linear compartmental modeling paradigm) to reliably derive an optimum antibody dose for a given patient.

²²⁵Ac is an alpha particle-emitting radioisotope. Although alpha particles-emitters are not yet in widespread clinical use, they have unique and highly advantageous physical and biological properties for targeted therapy: (1) their ranges in tissues are very short (of the order of one hundredth of a millimeter or approximately one cell radius) and thus will deliver their radiation doses very locally and very selectively to the targeted tumor cells with little or no significant irradiation of nearby normal cells; and (2) their very high so-called linear energy transfer (or LET) and resulting ionization density means that as few a single alpha-particle traversing a tumor-cell nucleus can kill the cell. Alpha-particles emitting radionuclides such as ²²⁵Ac are therefore highly attractive therapeutic payloads for application to the strategy described herein. And, to reiterate, the identical biodistributions of ⁸⁹Zr-DFO-hu11B6 and ²²⁵Ac-DOTA-hu11B6 antibody strongly support the clinical feasibility of this novel strategy.