Pretargeted Imaging and Therapy

Abstract

In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.

Keywords: biotin; bispecific antibody; click chemistry; multistep targeting; pretargeting; streptavidin.

FIGURE 1.

Schematic for in vivo pretargeting (A) and the 4 principal mechanisms of in vivo pretargeting (B).

FIGURE 2.

Structure of biotin (A); ribbon structure of the streptavidin tetramer (B); 3 different types of streptavidin-biotin pretargeting strategies (C–E); and γ-camera image of a patient with B-cell Hodgkin lymphoma injected with an anti-CD20-SA fusion protein and, 24 h later, ¹¹¹In-DOTA-biotin (F). Sites of active tumor involvement are indicated by arrows. (Reprinted with permission of (10).)

FIGURE 3.

Schematics of in vivo pretargeting strategies based on chemically linked Fab′ fragments (A), a divalent radiometal chelate hapten (B), an IgG–single-chain variable fragment (ScFv) construct (C), and an HSG-binding Tri-Fab (D); structure of the divalent IMP288 HSG hapten (E); pretargeted immuno-PET image of a patient with metastatic breast cancer recorded after the administration of 120 nmol of TF2 and, 30 h later, 3 nmol of ⁶⁸Ga-IMP288 (F). (Adapted and reprinted with permission of (22).)

FIGURE 4.

Structure of DNA, RNA, MORF, and PNA oligonucleotides (A); a pretargeted SPECT image of subcutaneous transplanted human islet cells (white arrow) in a mouse administered a MORF-modified variant of the islet-cell–specific HPi1 antibody followed by a ^99mTc-labeled complementary MORF radioligand (adapted and reprinted with permission from (26)) (B); and pretargeted SPECT images of mice bearing subcutaneous SKOV3 xenografts administered a directly radiolabeled ¹¹¹In-Z_HER2:K58 Affibody molecule (left), a PNA-modified Z_HER2-HP1 Affibody molecule followed by complementary ¹¹¹In-HP2 radioligand (center), and a ¹¹¹In-HP2 radioligand alone (right) (C). K = kidney; T = tumor (adapted and reprinted with permission from (30)).

FIGURE 5.

The IEDDA ligation (A); the 2 components of IEDDA-based pretargeting system: a TCO-bearing immunoconjugate and a tetrazine-modified radioligand (B); SPECT/CT image of an LS174T tumor-bearing mouse pretargeted with CC49-TCO and ¹¹¹In-DOTA-tetrazine (reprinted with permission of reference (34)) (C); and a longitudinal study of normalized tumor volume in mice bearing BxPC3 pancreatic ductal adenocarcinoma xenografts treated with a PRIT regimen composed of 5B1-TCO and ¹⁷⁷Lu-DOTA-PEG₇-tetrazine (reprinted with permission of (41)) (D).