111In/125/131I-Labeled anti-mucin-1 murine, chimeric or humanized antibody hPAM4

Excerpt

Mucins (MUC) are a distinct class of transmembrane glycoproteins (designated as MUC1, MUC3A, MUC3B, MUC4, etc.) that are expressed primarily by the glandular and ductal cells of the epithelium in the human body and are known to modulate the tumorigenicity, progression, and pathogenesis of different cancers (1). The structure, physiological function, and process of promoting the development of malignancies by MUCs, particularly MUC1 and MUC4, are discussed in detail by Bafna et al. (1). MUC1 has been shown to be characteristically overexpressed by pancreatic adenocarcinoma (PAC) cells and is not detectable in normal pancreatic ducts or other normal tissues, or during an incident of pancreatitis (2). Because it is detectable only in the serum of patients suffering from PAC, it was suggested recently that the MUC1 antigen can be used as a biomarker for the early detection this malignancy (3, 4).

The majority of individuals suffering from PAC do not survive for more than 1 year after diagnosis, and <1% of these patients live beyond 5 years (5). Although surgical resection of the cancer is a possible treatment for this disease, only 10%–25% of the patients are considered suitable for this treatment because, by the time that the neoplasm is detected, the malignancy has metastasized and the tumor load in the patient is too high to warrant surgery (5). Patients with nonresectable PAC are treated either with gemcitabine or radiotherapy; however, these treatments are not curative and only prolong survival and improve the quality of life of the patient (5). The detection of this invasive cancer at an early stage would facilitate proper staging of the disease, which could be followed either by surgical resection of the tumor or the initiation of a vigorous treatment regimen that could possibly improve patient prognosis (6).

More than a decade ago, a ¹³¹I-labeled murine monoclonal antibody, PAM4 ([¹³¹I]-mPAM4), directed against a mucin (later identified to be MUC1 (5)) was reported to detect human xenograft PAC tumors in mice with high specificity and, compared to controls, significantly extended the survival time of the animals when used for radiotherapy of the cancer (7-9). In a preliminary study, [¹³¹I]-PAM4 was demonstrated to detect the primary and the metastasized pancreatic carcinoma tumors in humans, and there was a low nonspecific uptake of the tracer in the liver, spleen, and bone marrow of the patients (10). In another study, a chimeric form of PAM4 (cPAM4) was labeled with ¹²⁵I and ¹¹¹In to obtain [¹²⁵I]-cPAM4 and [¹¹¹In]-cPAM4, respectively, and the biodistribution of these labeled mAbs was investigated in mice bearing human xenograft PAC tumors (11). Recently, Gulec et al. studied the biodistribution of ¹¹¹In-labeled humanized PAM4 ( [¹¹¹In]-hPAM4) in a phase I clinical trial (2).