Phase I Trial of <sup>131</sup>I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients

D’Huyvetter, Matthias; Vos, Jens De; Caveliers, Vicky; Vaneycken, Ilse; Heemskerk, Johannes; Duhoux, François; Fontaine, Christel; Vanhoeij, Marian; Windhorst, Albert D.; Aa, Frank van der; Hendrikse, N. Harry; Eersels, Jos; Everaert, Hendrik; Gykiere, Pieterjan; Devoogdt, Nick; Raes, Geert; Lahoutte, Tony; Keyaerts, Marleen

doi:10.2967/jnumed.120.255679

Cited by 75 publications

(58 citation statements)

References 21 publications

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“…Although high kidney accumulation of a radioligand may not affect the diagnostic decision, it will cause unexpected nephrotoxicity when the radioligand is used for therapeutic purposes. A recent clinical trial has shown the therapeutic potential of 131 I-labeled sdAb [26]. The high kidney accumulation of [ 68 Ga]Ga-NOTA-Nb1053 largely resided in the renal cortex (Fig.…”

Section: Strategies Reducing Kidney Accumulation Of [ 68 Ga]ga-nota-nb1053mentioning

confidence: 99%

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Wang

Chen

Hou

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Multiple myeloma (MM) remains incurable and its diagnosis relies heavily on bone marrow aspiration and biopsy. CD38 is a glycoprotein highly speci c for MM. Antibody therapeutics (e.g., daratumumab) targeting CD38 have shown encouraging e cacy in treating MM, either as a monotherapy agent or in combination with other regimens. However, e cient strati cation of patients who might bene t from daratumumab therapy and timely monitoring of the therapeutic responses are still clinical challenges. This work aims to devise a CD38-targeted imaging strategy and assess its value in diagnosing MMs.Methods By labeling a CD38-speci c single domain antibody (Nb1053) with 68 Ga (t 1/2 = 1.1 h), we developed a CD38-targeted immuno-positron emission tomography (immunoPET) imaging probe [ 68 Ga]Ga-NOTA-Nb1053. The probe was developed with good radiochemical yield (> 50%), excellent radiochemical purity (> 99%), and immunoreactivity (> 95%). The diagnostic accuracy of the probe was thoroughly investigated in preclinical MM models.Results ImmunoPET imaging with the probe speci cally depicted all the subcutaneous and orthotopic MM lesions, outperforming the traditional 18 F-uorodeoxyglucose PET and the nonspeci c [ 68 Ga]Ga-NOTA-NbGFP immunoPET. More importantly, daratumumab preloading signi cantly reduced [ 68 Ga]Ga-NOTA-Nb1053 uptake in the disseminated bone lesions, indicating the overlapping targeting epitopes of [ 68 Ga]Ga-NOTA-Nb1053 with that of daratumumab. Furthermore, premedication with sodium maleate or fructose signi cantly decreased kidney retention of [ 68 Ga]Ga-NOTA-Nb1053 and improved the diagnostic value of the probe in lymphoma models. ConclusionThis work successfully developed a novel CD38-targeted immunoPET imaging approach that enabled precise visualization of CD38 and diagnosis of MMs. Upon clinical translation, [ 68 Ga]Ga-NOTA-Nb1053 immunoPET may serve as a valuable CD38-targeted molecular imaging toolbox, facilitating early diagnosis of MM and precise assessment of the therapeutic responses.

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Section: Strategies Reducing Kidney Accumulation Of [ 68 Ga]ga-nota-nb1053mentioning

confidence: 99%

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Wang

Chen

Hou

et al. 2021

Eur J Nucl Med Mol Imaging

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“…Adverse effects were absent, and sternal metastatic regions were clearly identified for 24 h after treatment in both single-photon emission computed tomography (SPECT) and computed tomography (CT) imaging. 82 A similar phase I trial was conducted for 68 Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid ( 68 Ga-NOTA)-anti-HER2 VHH1, which additionally underwent positron emission tomography (PET) imaging. Fast blood clearance was observed, and the tracer accumulation was substantial for identifying most sites of disease.…”

Section: Nanobodiesmentioning

confidence: 99%

Extending traditional antibody therapies: Novel discoveries in immunotherapy and clinical applications

Shin

Kim

2021

Molecular Therapy - Oncolytics

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Immunotherapy has been well regarded as one of the safer and antigen-specific anti-cancer treatments compared to first-generation chemotherapy. Since Coley's discovery, researchers focused on engineering novel antibody-based therapies. Including artificial and modified antibodies, such as antibody fragments, antibody-drug conjugates, and synthetic mimetics, the variety of immunotherapy has been rapidly expanding in the last few decades. Genetic and chemical modifications to monoclonal antibody have been brought into academia, in vivo trials, and clinical applications. Here, we have looked around antibodies overall. First, we elucidate the antibody structure and its cytotoxicity mechanisms. Second, types of therapeutic antibodies are presented. Additionally, there is a summarized list of US Food and Drug Administration (FDA)-approved therapeutic antibodies and recent clinical trials. This review provides a comprehensive overview of both the general function of therapeutic antibodies and a few main variations in development, including recent advent with the proposed mechanism of actions, and we introduce types of therapeutic antibodies, clinical trials, and approved commercial immunotherapeutic drugs. STRUCTURES AND FUNCTIONS OF THERAPEUTIC ANTIBODY Structure of therapeutic antibodyIgs have five major classes where each class has a unique sequence of heavy chain (HC) constant regions: IgA, IgD, IgE, IgG, and IgM. 10 IgG, which has a g HC, comprises 80% of total antibodies in serum,

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“…Several antibodies targeting this immune checkpoint have been granted regulatory approval in recent years and there is an increasing need for imaging agents for the diagnosis and monitoring of PD-(L)1 positive malignancies. Several sdAbs targeting cancer biomarkers such as PD-L1 or human epidermal growth factor receptor 2 are currently in clinical development [40][41][42].…”

Section: Introductionmentioning

confidence: 99%

NHS-Functionalized THP Derivative for Efficient Synthesis of Kit-Based Precursors for 68Ga Labeled PET Probes

et al. 2021

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Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the radiometal gallium-68 (68Ga). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga at room temperature, neutral pH, and micromolar ligand concentrations, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. With the aim to produce an N-hydroxysuccinimide-(NHS)-THP reagent for kit-based 68Ga-labeling and PET imaging, THP-derivatives were designed and synthesized to exploit the advantages of NHS chemistry for coupling with peptides, proteins, and antibodies. The more stable five-carbon atoms linker product was selected for a proof-of-concept conjugation and radiolabeling study with an anti-programmed death ligand 1 (PD-L1) camelid single domain antibody (sdAb) under mild conditions and further evaluated for site-specific amide bond formation with a synthesized glucagon-like peptide-1 (GLP-1) targeting peptide using solid-phase synthesis. The obtained THP-GLP-1 conjugate was tested for its 68Ga chelating ability, demonstrating to be a promising candidate for the detection and monitoring of GLP-1 aberrant malignancies. The obtained sdAb-THP conjugate was radiolabeled with 68Ga under mild conditions, providing sufficient labeling yields after 5 min, demonstrating that the novel NHS-THP bifunctional chelator can be widely used to easily conjugate the THP moiety to different targeting molecules (e.g., antibodies, anticalins, or peptides) under mild conditions, paving the way to the synthesis of different imaging probes with all the advantages of THP radiochemistry.

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Phase I Trial of ¹³¹I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients

Cited by 75 publications

References 21 publications

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Extending traditional antibody therapies: Novel discoveries in immunotherapy and clinical applications

NHS-Functionalized THP Derivative for Efficient Synthesis of Kit-Based Precursors for 68Ga Labeled PET Probes

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Phase I Trial of 131I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients

Cited by 75 publications

References 21 publications

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Extending traditional antibody therapies: Novel discoveries in immunotherapy and clinical applications

NHS-Functionalized THP Derivative for Efficient Synthesis of Kit-Based Precursors for 68Ga Labeled PET Probes

Contact Info

Product

Resources

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Phase I Trial of ¹³¹I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients