Complete remissions of HER2-positive trastuzumab-resistant xenografts using a potent [225Ac]Ac-labeled anti-HER2 antibody-drug radioconjugate.

Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted alpha therapies. Antibody-drug conjugates (ADCs) are highly cytotoxic. Combining [225Ac]Ac with ADC to develop an antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, is expected to be more effective than its ADC (trastuzumab-PEG6-DM1) against breast cancer (BC).

Preclinical safety and effectiveness of a long-acting somatostatin analogue [Ac]Ac-EBTATE against small cell lung cancer and pancreatic neuroendocrine tumors.

Purpose: We report the preclinical evaluation of potent long-acting [Ac]Ac-EBTATE against SSTR2-positive small cell lung cancer (SCLC) and pancreatic neuroendocrine tumors (pan-NETs).

Methods: The pharmacokinetic, biodistribution, and safety studies were evaluated in healthy female and/or male BALB/c mice after intravenous injections of [Ac]Ac-EBTATE. Further biodistribution and radioligand therapy were investigated in female athymic BALB/c nude mice bearing high or low SSTR2-expressing subcutaneous SCLC models NCI-H524 or NCI-H727, respectively, and in a pan-NET model QGP1.

Efficacy of [Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors.

β-emitting Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability.

Effectiveness of [Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer.

Purpose: To evaluate the imaging and therapeutic properties (theranostic) of Cu-labeled anti-human epidermal growth factor receptor II (HER2) monoclonal antibody trastuzumab against HER2-positive breast cancer (BC).

Methods: We conjugated trastuzumab with p-SCN-Bn-NOTA, 3p-C-NETA-NCS, or p-SCN-Bn-DOTA, and radiolabeled with [Cu]CuCl. Immunoconjugate internalization was evaluated in BT-474, JIMT-1 and MCF-7 BC cells.

Biparatopic anti-HER2 drug radioconjugates as breast cancer theranostics.

Background: HER2 is overexpressed in 25-30% of breast cancer. Multiple domains targeting of a receptor can have synergistic/additive therapeutic effects.

Methods: Two domain-specific ADCs trastuzumab-PEG-DM1 (domain IV) and pertuzumab-PEG-DM1 (domain II) were developed, characterised and radiolabeled to obtain [Zr]Zr-trastuzumab-PEG-DM1 and [Cu]Cu-pertuzumab-PEG-DM1 to study their in vitro (binding assay, internalisation and cytotoxicity) and in vivo (pharmacokinetics, biodistribution and immunoPET/SPECT imaging) characteristics.

Engineering of a Fully Human Anti-MUC-16 Antibody and Evaluation as a PET Imaging Agent.

Antibodies that recognize cancer biomarkers, such as MUC16, can be used as vehicles to deliver contrast agents (imaging) or cytotoxic payloads (therapy) to the site of tumors. MUC16 is overexpressed in 80% of epithelial ovarian cancer (EOC) and 65% of pancreatic ductal adenocarcinomas (PDAC), where effective ‘theranostic’ probes are much needed. This work aims to develop fully human antibodies against MUC16 and evaluate them as potential immuno-PET imaging probes for detecting ovarian and pancreatic cancers.

Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates.

Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal cancer (CRC) xenografts. We developed Zr-matuzumab and performed quality control in EGFR-positive DLD-1 cells.

3p-C-NETA: A versatile and effective chelator for development of AlF-labeled and therapeutic radiopharmaceuticals.

: Radiolabeled somatostatin analogues ( [Ga]Ga-DOTATATE and [Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [F]AlF-NOTA-octreotide, a promising F-labeled somatostatin analogue and potential alternative for Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar ( AlF-method in combination with therapeutic radiometals Bi/Lu) or identical ( complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients.