Dextran and PEG coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal Antibodies, scFv, and peptides conjugated to 20-nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NP's can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 nm and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm Superparamagnetic Iron Oxide (SPIO) NP. SPIO NP 20-nm, NF NP 30-and 100-nm were conjugated to 111 In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NP's using 25μg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body, blood and tissue data were collected at 4, 24, and 48 hours. The preparations used for animal study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40−60% compared to 111 In-ChL6. Specific activities of the doses were 20−25μCi/2.2 mg and 6−11μg of MAb/2.2 mg of NP. Mean tumor uptakes (% ID/g ± SD) of each SPIO 20nm, NF 30nm, and 100nm RINP at 48h were 9.00 ± 0.8 (20nm), 3.0 ± 0.3 (30nm), and 4.5 ± 0.8 (100nm) respectively; the ranges of tissue uptakes were liver (16−32 ± 1 − 8), kidney (7.0−15 ± 1) spleen (8−17 ± 3 − 8) lymph nodes 5 − 6 ± 1 −2) and lung (2.0− 4 ± 0.1 − 2). In conclusion, this study demonstrated that 100 nm NF NP could be conjugated to 111 In-MAb so that the resulting RINP had characteristics suitable for AMF therapy. Although 100-nm RINP targeted tumor less than 20-nm SPIO RINP, their heating capacity is typically 6 times greater, suggesting the 100-nm NF RINP could still deliver better therapy with AMF.

Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer.

No abstract

Purpose: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. Experimental Design: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. 111In/ 90 Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgenindependent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage ( Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1epitopes. Results: The nonmyeloablative maximum tolerated dose of 90 Y-m170 was 0.74 GBq/m 2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m 2 of 90 Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. Conclusions: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90 Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients.Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.Although localized prostate cancer is curable, metastatic hormone-independent prostate cancer is usually fatal. Better understanding of this disease has yielded information useful in designing new therapeutic strategies (1, 2). Studies of epithelial cancer biology have provided insights into the relationship of abnormal glycoproteins and prostate cancer grade of relevance for tumor targeting (3 -7).Cancer-related aberrations in MUC1 epithelial mucin present unique epitopes that can provide targets for site-specific therapy for many epithelial cancers. Normal MUC1 is api...

Background. There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received131 I chimeric‐L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement‐dependent tumor cytolysis with human serum, and antibody‐dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a “therapeutic window” of increased vascular permeability, allowing more131 I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6. Methods. Nine patients with metastatic breast cancer were treated on a therapy protocol and received imaging and therapy doses of 131 I ChL6 on two sequential days at 4 week intervals. During each treatment cycle, serum cytokines, complement, albumin, and 131 I ChL6 blood clearance were monitored, peripheral blood mono‐nuclear cell activation was assessed, and tumor uptake and response were documented. Results. After L6 or ChL6 was infused, patients demonstrated immediate serum‐complement activation, manifested by rapidly decreasing levels of serum complements 3 and 4. Tumor uptake of the second 131 I MoAb (therapeutic) injection, given after the second daily injections of 200 mg MoAb, was usually higher than the tumor uptake of the first 131 I MoAb (imaging) dose given after a single 200 mg infusion of MoAb. Although serum complement frequently decreased after the first 50–100 mg dose of L6 or ChL6, elevation of soluble interleukin‐2 receptor (IL‐2R) in serum was seen only in patients who received 150 mg or more of L6 or ChL6. In the nine treated patients, with only one exception, the higher grade of therapeutic tumor response was seen in patients with a greater increase in IL‐2R levels. Conclusions. The clinical importance of understanding these mechanisms is emphasized by the occurrence of measurable tumor regressions in five of the first nine advanced metastatic breast cancer patients treated in this manner. Absence of pulmonary edema and delayed release of dose‐dependent IL‐2R suggest that targeting of the pulmonary endothelium by L6 or ChL6 is not the major cause of the observed biologic effects. This unique response of a solid tumor to radioimmunoconjugate therapy may be secondary to both the increased delivery of the radioimmunoconjugate to tumor cells caused by enhanced vascular permeability, and to synergistic effects of radiation and activated effector cell mechanisms. Cancer 1994; 73:1023–32.