Pretargeting: A Path Forward for Radioimmunotherapy

Abstract

Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high-therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin-streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics.

Keywords: general oncology; multistep; pretargeted radioimmunotherapy; radioimmunotherapy; radionuclide therapy; radiopharmaceuticals.

FIGURE 1.

Comparison of conventional radioimmunotherapy and PRID/PRIT and compatible vector survey. (A) Injection of radioimmunoconjugate (left) leads to low TIs, especially in hematopoietic and highly perfused tissues. With 3-step BsAb pretargeting (middle), BsAb is administered, followed 1 d later by CA to quickly reduce circulating BsAb. During final step, administered radiocarrier (e.g., radiohapten) is captured by intratumoral BsAb or rapidly cleared. A 2-step approach (right) is feasible with SADA BsAb innovation. (Adapted from ( 153 )). (B) Select bispecific antitumor/antiradiocarrier vectors.

FIGURE 2.

Initial PRID studies of tumors in patients. (A) BsAb pretargeting system. Planar posterior pelvic scan (coronal view) of patient with recurrent CRC invading right sacral area was obtained 3 d after injection of ¹¹¹In-hapten. a =tumor; b =kidneys; c =spine; d = iliac crest. (Reprinted with permission of ( 20 ).) (B) Biotin–streptavidin pretargeting system. Anterior chest and upper abdomen image (coronal view) of patient with recurrent squamous cell carcinoma of right lung was obtained 2 h after injection of ¹¹¹In-biotin. a = tumor; b = kidneys; c = bladder. (Reprinted from ( 26 ).)

FIGURE 3.

BsAb pretargeting with DNL BsAb or with SADA BsAb platform. (A) Structure of tri-Fab TF4 made by DNL method and associated HSG hapten, IMP-288. DNL BsAb has single binding site for hapten and 2 binding sites for tumor antigen. (Reprinted with permission of ( 154 ).) (B) Structure of anti-GD2/anti-DOTA SADA BsAb and ²²⁵Ac-DOTA-hapten (reprinted from ( 123 )) and ¹⁷⁷Lu-aminobenzyl-DOTA (reprinted with permission of ( 127 )). SADA BsAb has 4 binding sites for both DOTA hapten and tumor antigen. hA20 = humanized anti-CD20 IgG hA20 (veltuzumab); VH = heavy chain variable domain; VK = light chain variable domain; CH1 = heavy-chain constant domain 1; CK = light-chain constant domain; DDD2 = dimerization and docking domain with SEQ ID NO: 2; AD2 = anchoring domain with SEQ ID NO: 4.

FIGURE 4.

Select examples of recent clinical BsAb PRID with DNL TF2 and radiolabeled IMP288 (TF2/IMP288). (A) Scintigraphic images (axial views) of CRC patient imaged with TF2/¹¹¹In-IMP288, with highly specific targeting of primary colon tumor, confirmed by CT and ¹⁸F-FDG PET/CT (B and C, respectively). (Reprinted from ( 108 ).) (D) PET image (coronal view) of MTC patient imaged with TF2/⁶⁸Ga-IMP288, with maximum-intensity-projection (MIP) image showing several pathologic lesions. (Reprinted from ( 115 ).)

FIGURE 5.

Affibody pretargeting with PNAs (A) or bioorthogonal inverse electron-demand Diels–Alder click chemistry (B). (Portions reprinted from ( 133 , 155 ).)