99mTc-Ac-Lys(DTPA)-Tyr-Lys(DTPA)-Lys(thiosemicarbazonyl-glyoxyl-cysteinyl-)-NH2 (IMP-192)

Excerpt

The majority of individuals suffering from pancreatic adenocarcinoma (PAC) do not survive for more than 1 year after diagnosis and fewer than 1% of these patients live beyond 5 years (1). Although surgical resection of the cancer is a possible intervention for this disease only 10 – 25% of the patients are considered suitable for this treatment because usually by the time that neoplasm is detected the malignancy has metastasized to other organs and the tumor load in the patient is too high to warrant surgery (2). Patients with nonresectable PAC are treated either with gemcitabine or radiotherapy or a combination of the two, however, these treatments are not curative because they only prolong survival and improve the quality of life of the patient (2). The detection of this cancer at an early stage can facilitate proper staging of the disease so that a suitable treatment regimen can be initiated to possibly improve patient prognosis (3). In this regard the monoclonal antibody (mAb), PAM4, which specifically targets mucin 1 (MUC1), a glycoprotein, that is overexpressed only in PAC tumors was developed, radiolabeled with ¹³¹I or ¹¹¹In and shown to detect neoplastic tumors with scintigraphy in patients having pancreatic malignancies (4). However, intact radiolabeled antibodies are of limited utility to visualize cancerous lesions due to their large size (~150 kDa) and long circulating half-life (5). To amplify the signal obtained from an imaging agent that can be used to detect malignant tumors noninvasively, investigators have developed and evaluated a variety of strategies in preclinical studies in animals such as pretargeting the cancer lesion with a suitable mAb (or its derivative) followed by exposing the animals to an appropriate radiolabeled small molecular weight ligand that targets the mAb or its derivative. This technique has been shown to generate a higher signal-to-noise ratios during imaging compared to ratios obtained with a directly labeled mAb alone (6-8). Use of the pretargeting technique for the imaging and therapy of cancer has been discussed elsewhere (9, 10).

Cardillo et al. developed a bispecific F(ab’)₂ mAb (bsPAM4; bsmAb) by cross-linking a PAM4 Fab’ fragment (binds the MUC-1 antigen) to a murine anti-indium-diethylenetriaminepentaacetic acid (DTPA) mAb Fab’ fragment (binds the peptide heptan antigen) and used the unlabeled bsmAb to pretarget human CaPan-1 cell xenograft PAC tumors in nude mice (4). After the bsmAb was cleared from blood circulation the animals were injected with a radiolabeled peptide heptan to visualize the PAC lesions with whole body scintigraphy. To confirm the tumor targeting specificity and delivery of bsPAM4 to the tumor (the pretargeting bsmAb) the biodistribution of this bsmAb was investigated in mice bearing human PAC tumors using ¹²⁵I-labeled bsPAM4 ([¹²⁵I]-bsPAM4) (4). Subsequently two groups of animals pretargeted with bsPAM4 were separately injected with radiolabeled peptide haptens, ¹¹¹In-labeled Ac-Phe-Lys(DTPA)-Tyr-Lys(DTPA)-NH₂ ([¹¹¹In]-IMP-156) and ⁹⁹Tc-labeled Ac-Lys(DTPA)-Tyr-Lys(DTPA)-Lys(thiosemicarbazonyl-glyoxyl-cysteinyl-)-NH₂ ([^99mTc]-IMP-192), that specifically bind the anti-indium-DTAP mAb Fab’ arm of the bsmAb and the biodistribution of these radiolabeled peptides was investigated in the tumor bearing rodents. This chapter describes the biodistribution characteristics of [^99mTc]-IMP-192. The biodistribution of radioiodinated bsPAM4 in non-pretargeted mice (11) and the biodistribution and imaging studies performed with [¹¹¹In]-IMP-156 in mice pretargeted with bsPAM4 (12) are discussed in separate chapters of MICAD (www.micad.nih.gov).