Enhancement of the Therapeutic Index: From Nonmyeloablative and Myeloablative toward Pretargeted Radioimmunotherapy for Metastatic Prostate Cancer

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...

Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance

“…For antibody therapies utilizing radiometal and toxin conjugates, slow systemic clearance may cause dose limiting toxicities to the bone marrow and other healthy tissue [119,120]. Similarly, slow clearance may reduce the sensitivity of imaging or necessitate long waiting periods due to high background signals in the blood and other well perfused tissues [29].…”

MUC1 is a Promising Therapeutic Target for Prostate Cancer Therapy

“…Using MAbs DF3 and B27.29, Zellweger et al have shown that expression of human MUC1 (urinary mucin 1) slowly but gradually increased from BPH to prostatic intraepithelial neoplasia (PIN) and through the various stages of CaP [134]. DeNardo et al have tested MUC1 expression on CaP TMAs using three anti-MUC1 MAbs (BrE3, B27.29, and HMFG1), and found that the profile of BrE3 showed a strong correlation between CaP stage and increase in MUC1 staining (P<0.001) [135].…”

“…In another trial study, the 90 Y-m170 was further evaluated in androgen-independent CaP patients to determine MTD and efficacy of nonmyeloablative radioimmunotherapy (RIT) and myeloablative combined modality RIT with paclitaxel [135]. To enhance the tumor to liver therapeutic index, a cathepsin degradable MAb linkage ( 90 Y-DOTA-peptide-m170) was used in the combination therapy protocol.…”

Update: Recombinant Antibodies: From the Laboratory to the Clinic

“…121 The projected assembly of covalent tri-and tetravalent PEG-scFv complexes for pretargeted RIT in metastatic prostate cancer has also been described. 122 The MUC1-driven expression of the sodium iodide symporter in breast tumor xenografts led to increased radioactivity uptake by tumor cells. 123 A divalent scFv-angiotensin II fusion protein demonstrated improved tumor distribution in tumorbearing mice.…”