HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging

Abstract

Purpose The aim of the present paper is to review the role of HER2 antibodies, affibodies and nanobodies as vehicles for imaging and therapy approaches in breast cancer, including a detailed look at recent clinical data from antibody drug conjugates and nanobodies as well as affibodies that are currently under development. Results Clinical and preclinical studies have shown that the use of monoclonal antibodies in molecular imaging is impaired by slow blood clearance, associated with slow and low tumor uptake and with limited tumor penetration potential. Antibody fragments, such as nanobodies, on the other hand, can be radiolabelled with short-lived radioisotopes and provide high-contrast images within a few hours after injection, allowing early diagnosis and reduced radiation exposure of patients. Even in therapy, the small radioactively labeled nanobodies prove to be superior to radioactively labeled monoclonal antibodies due to their higher specificity and their ability to penetrate the tumor. Conclusion While monoclonal antibodies are well established drug delivery vehicles, the current literature on molecular imaging supports the notion that antibody fragments, such as affibodies or nanobodies, might be superior in this approach.

Site-Specific and Residualizing Linker for 18F Labeling with Enhanced Renal Clearance: Application to an Anti-HER2 Single-Domain Antibody Fragment

“…This is an important distinction with agents like 18 F-RL-I-5F7, noted above, that show excellent tumor uptake but at the expense of sustained kidney activity levels >100% ID/g (7). Indeed, renal activity levels for 18 F-5F7GGC were about 4-5 times lower than those for co-administered iso-125 I-SGMIB-5F7, heretofore possibly the radiolabeled sdAb investigated to date exhibiting the most rapid clearance (1,9,37). It is likely that this behavior reflects both the presence of an RBBE-cleavable linker as well as the rapidly clearing 6-18 F-fluoronicotinoyl moiety-containing catabolites (13).…”

“…Sodium 125 I-iodide [81.4 TBq (2200 Ci/mmol] in 0.1 N NaOH was obtained from Perkin-Elmer Life and Analytical Sciences (Boston, MA). N-succinimidyl 3-((1, 2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-iodobenzoate (Boc2-iso-SGMIB) and its tin precursor Nsuccinimidyl 3-((1, 2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(tri-n-butylstannyl)benzoate (Boc2-iso-SGMTB) were synthesized following reported methods (1).…”

“…Solvents were evaporated to yield 41.0 mg (92.7%, based on trifluoroacetate salt) of compound 6 as a white solid. Because of its extreme polarity, purification by reversed-phase HPLC was not feasible and thus it was carried over as such to the next step 1. H NMR (D2O, 400 MHz) δH =1.3-1.5 (m, 3H), 2.4-2.5 (t, 1H), 3.1-3.2 (t, 3H), 3.5-3.8 (m, 26H), 3.8-3.9 (s, 2H), 4.3-4.4 (t, 2H), 7.9−8.1 (d, 1H), 8.4-8.5 (d, 1H), 8.9-9.0(s,1H).…”

Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

“…The faster clearance of these smaller compounds can also offer an improved toxicity profile, though alternative dosing regimens will likely be required (i.e., administration more frequently than once every 3 to 4 weeks as is used with standard mAbs and ADCs) to achieve anti-tumor efficacy. There have been various small-format ADCs developed to target HER2; however, results of these clinical studies show that these small sized ADCs are better suited for use as theranostics in nuclear medicine due to their high affinity to the target and short biological half-life compared to use as therapeutic agents [177].…”

Enzymatic Methods for the Site-Specific Radiolabeling of Targeting Proteins

“…It is interesting to note that although the imaging tracers used in biomedical research and in clinical practice are generally based on small molecules and peptides, the research interest has shifted toward the development of radiolabeled naturally occurring or naturally inspired biomolecules, such as antibodies, especially IgG and their truncated counterparts (F(ab') 2 , Fab, scFv) as well as engineered mAb fragments (miniboby, diaboby, nanobody), and small protein scaffolds (affibody, etc.) [3,[9][10][11]. The utility of these biomolecules to treat cancer is due to their ability to bind tumor-associated antigens (e.g., HER2, EGFR, CD20, etc.)…”