Pretargeted Imaging and Therapy

Altai, Mohamed; Membreno, Rosemery; Tolmachev, Vladimir; Zeglis, Brian M.

doi:10.2967/jnumed.117.189944

Cited by 164 publications

(172 citation statements)

References 34 publications

(43 reference statements)

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“…3 In antibody pretargeting, the molecular uncoupling of the slowly clearing, targeting antibody from the radiolabel presents an opportunity to acquire images using faster decaying radionuclides such as 68 Ga ( t 1/2 = 68 min) and 18 F ( t 1/2 = 110 min). Direct comparisons to directly labeled methods suggest that pretargeting methods could reduce patient radiation exposure during imaging procedures by 1–2 orders of magnitude, 4 with benefits also possible for pretargeted radioimmunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Mandikian¹,

Rafidi²,

Adhikari³

et al. 2018

mAbs

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Antibody pretargeting is a promising strategy for improving molecular imaging, wherein the separation in time of antibody targeting and radiolabeling can lead to rapid attainment of high contrast, potentially increased sensitivity, and reduced patient radiation exposure. The inverse electron demand Diels-Alder ‘click’ reaction between trans-cyclooctene (TCO) conjugated antibodies and radiolabeled tetrazines presents an ideal platform for pretargeted imaging due to rapid reaction kinetics, bioorthogonality, and potential for optimization of both slow and fast clearing components. Herein, we evaluated a series of anti-human epidermal growth factor receptor 2 (HER2) pretargeting antibodies containing distinct molar ratios of site-specifically incorporated TCO. The effect of stoichiometry on tissue distribution was assessed for pretargeting TCO-modified antibodies (monitored by 125I) and subsequent accumulation of an 111In-labeled tetrazine in a therapeutically relevant HER2+tumor-bearing mouse model. Single photon emission computed tomography (SPECT) imaging was also employed to assess tumor imaging at various TCO-to-monoclonal antibody (mAb) ratios. Increasing TCO-to-mAb molar ratios correlated with increased in vivo click reaction efficiency evident by increased tumor distribution and systemic exposure of 111In-labeled tetrazines. The pharmacokinetics of TCO-modified antibodies did not vary with stoichiometry. Pretargeted SPECT imaging of HER2-expressing tumors using 111In-labeled tetrazine demonstrated robust click reaction with circulating antibody at ~2 hours and good tumor delineation for both the 2 and 6 TCO-to-mAb ratio variants at 24 hours, consistent with a limited cell-surface pool of pretargeted antibody and benefit from further distribution and internalization. To our knowledge, this represents the first reported systematic analysis of how pretargeted imaging is affected solely by variation in click reaction stoichiometry through site-specific conjugation chemistry.

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Section: Introductionmentioning

confidence: 99%

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Mandikian¹,

Rafidi²,

Adhikari³

et al. 2018

mAbs

View full text Add to dashboard Cite

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“…In the interest of being fair and current, it must be stated that practical solutions to overcome some of the inherent limitations of using full-length antibodies and antibody fragments as tumor-targeting vectors have been sought. For example, pretargeted immunoPET imaging and pretargeted radioimmunotherapy (PRIT) can significantly reduce the off-target radiation dose for antibodies that target non-internalizing tumor-associated antigens(25–28). In pretargeted imaging studies, tumors can be delineated in PET scans at time points as early as 4–24 h after the injection of the small molecule radioligand (29–32).…”

Section: Selecting Antibody-based Tumor Targeting Vectors As Radiophamentioning

confidence: 99%

“…The anti-albumin variable fragment resulted in an increase serum half-life in both mice (t 1/2 = 2.9 days) and cynomolgus monkeys (t 1/2 = 7.9 days) (133). A sequential delivery approach, referred as pretargeting, has also been developed in order to improve therapeutic indices (Figure 7B) (25). The separation of the antibody administration from the radionuclide has been explored clinically using a non-radiolabelled bispecific monoclonal antibody (TF2) and a radiolabelled ( 111 In for imaging and 177 Lu for therapy) hapten peptide (IMP288) (134).…”

Section: Radionuclides For Radioimmunotherapy – Particle Selectionmentioning

confidence: 99%

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Preclinical optimization of antibody‐based radiopharmaceuticals for cancer imaging and radionuclide therapy—Model, vector, and radionuclide selection

Carter

Poty

Sharma

et al. 2018

Labelled Comp Radiopharmac

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Intact antibodies and their truncated counterparts (eg, Fab, scFv fragments) are generally exquisitely specific and selective vectors, enabling recognition of individual cancer-associated molecular phenotypes against a complex and dynamic biomolecular background. Complementary alignment of these advantages with unique properties of radionuclides is a defining paradigm in both radioimmunoimaging and radioimmunotherapy, which remain some of the most adept and promising tools for cancer diagnosis and treatment. This review discusses how translational potency can be maximized through rational selection of antibody-nuclide couples for radioimmunoimaging/therapy in preclinical models.

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“…A low-molecular-weight radioligand is subsequently administered and diffuses into the tumor, binding to the antigen-associated pretargeting conjugate. The rapid clearance of any excess radioligand results in improved tumor-to-normal-tissue ratios and lower radiation doses to healthy organs (42). Interaction between the pretargeted antibody and the radioligand uses the extraordinarily high affinity of avidin (or streptavidin) for biotin (43), bispecific antibodies (44), or bioorthogonal chemistry (45).…”

Section: A-emitters For Radiotherapy • Poty Et Altargeted α-Therapy:mentioning

confidence: 99%

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

et al. 2018

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Learning Objectives: On successful completion of this activity, participants should be able to (1) cite α-emitter families available for therapeutic use and understand their current production limit; (2) consider radiation safety concerns when handling α-emitters; and (3) overcome radiolabeling and daughter redistribution hurdles with the approaches described in this educational review. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through June 2021.With a short particle range and high linear energy transfer, α-emitting radionuclides demonstrate high cell-killing efficiencies. Even with the existence of numerous radionuclides that decay by α-particle emission, only a few of these can reasonably be exploited for therapeutic purposes. Factors including radioisotope availability and physical characteristics (e.g., half-life) can limit their widespread dissemination. The first part of this review will explore the diversity, basic radiochemistry, restrictions, and hurdles of α-emitters. Radi onuclide strategies for curative therapy, disease control, or palliation are positioned to constitute a major portion of nuclear medicine. The range of available therapeutic radioisotopes, including a, b, or Auger electron emission, has considerably expanded over the last century (1). Matching the particle decay pathway, effective range, and relative biological effectiveness to tumor mass, size, radiosensitivity, and heterogeneity is the primary consideration for maximizing therapeutic efficacy. b-emitting radioisotopes have the longest particle pathlength (#12 mm) and lowest linear energy transfer (LET) (;0.2 keV/mm), supporting their effectiveness in medium to large tumors (Fig. 1). Although the long b-particle range is advantageous in evenly distributing radiation dose in heterogeneous tumors, it can also result in the irradiation of healthy tissue surrounding the tumor site. Conversely, Auger electrons have high LET (4-26 keV/mm) but a limited pathlength of 2-500 nm that restricts their efficacy to single cells, thus requiring the radionuclide to cross the cell membrane and reach the nucleus. Finally, a-particles have a moderate pathlength (50-100 mm) and high LET (80 keV/mm) that render them especially suitable for small neoplasms or micrometastases. A recent clinical study highlighted the ability of a-radiotherapy to overcome treatment resistance to b-particle therapy, prompting a paradigm shift in the approach toward radionuclide therapy (2).For optimized therapeutic efficacy, the a-cytotoxic payload is expected to accumulate selectively in diseased tissue and deliver a suf...

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Pretargeted Imaging and Therapy

Cited by 164 publications

References 34 publications

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Preclinical optimization of antibody‐based radiopharmaceuticals for cancer imaging and radionuclide therapy—Model, vector, and radionuclide selection

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

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