Wang, Kumar, and Ding et al. demonstrated the anticancer efficacy of intraductally administered HB21(Fv)-PE40, a single-chain immunotoxin (IT) in mammary-in-duct models of DCIS using MCF7 and SUM225 grown in NOD/SCID/gamma mice. Intraductal, but not intraperitoneal, treatment with HB21(Fv)-PE40 eliminated tumors in 100% of the MCF7 tumor-bearing mice; it also significantly reduced tumor burden and, in some cases, eliminated tumors in aggressive SUM225 tumor-bearing mice. HB21(Fv)-PE40 was undetectable in plasma 5 to 30 min after intraductal IT administration.

Contributed by Shishir Pant

ABSTRACT: The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 _g HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 _g/teat). MCF7 tumor-bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (2) Depart

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (2) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. (3) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. (4) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. (5) Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892. (6) Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892. (7) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. (8) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. (9) Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892. (10) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.