Therapeutic Applications of Pretargeting

Abstract

Targeted therapies, such as radioimmunotherapy (RIT), present a promising treatment option for the eradication of tumor lesions. RIT has shown promising results especially for hematologic malignancies, but the therapeutic efficacy is limited by unfavorable tumor-to-background ratios resulting in high radiotoxicity. Pretargeting strategies can play an important role in addressing the high toxicity profile of RIT. Key to pretargeting is the concept of decoupling the targeting vehicle from the cytotoxic agent and administrating them separately. Studies have shown that this approach has the ability to enhance the therapeutic index as it can reduce side effects caused by off-target irradiation and thereby increase curative effects due to higher tolerated doses. Pretargeted RIT (PRIT) has been explored for imaging and treatment of different cancer types over the years. This review will give an overview of the various targeted therapies in which pretargeting has been applied, discussing PRIT with alpha- and beta-emitters and as part of combination therapy, plus its use in drug delivery systems.

Keywords: biotin; bispecific antibody; cancer; click chemistry; nanoparticles; oligonucleotides; pretargeting; radioimmunotherapy; streptavidin; targeted radionuclide therapy.

Figure 1

The pretargeting concept. (A) Different steps of the pretargeting approach. The targeting vector consists of a binding domain, a linker, and a pretargeting moiety (dark blue) and the small molecule of a complementary pretargeting moiety, a linker, and an effector (e.g., a radionuclide) (light blue). (B) The four most commonly applied pretargeting methods are illustrated with an antibody as target vector and a radionuclide as effector. I) The streptavidin–biotin approach. The dotted circles represent the other three biotin binding sites of (strept)avidin. II) Pretargeting using bispecific antibodies with a binding site for a radiolabeled hapten. Two small molecules are shown with on the left a monovalent hapten and on the right a bivalent hapten that could bridge two antibodies (i.e., affinity enhancement system). III) Pretargeting based on oligonucleotide hybridization. The backbone can for example exist of morpholine rings (i.e., MORF/cMORF pretargeting). IV) The click chemistry technology. A covalent bond-forming approach between, for example, trans-cyclooctene and tetrazine.

Figure 2

Representative example of the use of multiple pretargeted radioimmunotherapy (PRIT) treatment cycles. Survival curve of mice bearing human CRC tumors divided in groups receiving either 1, 2, or 3 cycles of PRIT with anti-CEA × anti-HSG bsAbs and lutetium-177-labeled DOTA-di-HSG peptide or PBS. This research was originally published in JNM. Schoffelen et al. Pretargeted 177Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice. J Nucl Med. 2010, 51, 1780–1787. © SNMMI. [55].

Figure 3

Representative images demonstrating feasibility of PRIT for internalizing targets. SPECT/CT images (from left to right: coronal and transverse slices through center of tumor, maximum intensity projection) of human breast cancer xenografts 24 h postinjection of one cycle of lutetium-177-labeled DOTA-Bn hapten pretargeted with either control IgG-DOTA or anti-HER2 × anti-DOTA bsAb. The white arrow is pointed at the tumor and the yellow arrow at the bladder. The color scale represents the percentage of injected activity per cc. This research was originally published in Theranostics. Cheal et al. Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of her2-positive breast carcinoma. Theranostics 2018, 8, 5106–5125. [103].

Figure 4

Amplification of the nanoconjugates (NCs) tumor targeting performance via metabolic engineering of tumor cells. Whole-body fluorescence imaging of mice bearing human CRC tumors left and right at 1, 6, 24, 48, and 72h after injection of the azido-/Cy5-NCs. The right tumor was injected with PBS as control and the left tumor was injected with Ac₄ManDBCO daily for three days prior to injection of the NC to label the cancer cells. The arrows point at the tumors. This research was originally published in Theranostics. Wang et al. In vivo targeting of metabolically labeled cancers with ultra-small silica nanoconjugates. Theranostics 2016, 6, 1467–1476. [149]