Anti-Human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation

Bridoux, Jessica; Broos, Katrijn; Lecocq, Quentin; Debie, Pieterjan; Martin, Charlotte; Ballet, Steven; Raes, Geert; Neyt, Sara; Vanhove, Christian; Breckpot, Karine; Devoogdt, Nick; Caveliers, Vicky; Keyaerts, Marleen; Xavier, Catarina

doi:10.3390/biom10101388

Cited by 53 publications

(62 citation statements)

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“…Optimally this nanobody needs to be labeled with a short-lived PET-isotope such as 68 Ga or 18 F using new or established radiochemistry procedures (25,(41)(42)(43). Extrapolating from our still ongoing clinical trials with a 68 Ga-labeled anti-HER2 nanobody breast cancer PET-tracer ( 26) and an anti-CD206 nanobody macrophage PET-tracer (25), we are hopeful that the future clinical anti-LAG-3 nanobody PET-tracer will also be safe, sensitive and will conveniently provide a whole-body picture of LAG-3 expression levels in a same-day imaging procedure with acceptable dosimetry levels.…”

Section: Discussionmentioning

confidence: 99%

Single-Domain Antibody Nuclear Imaging Allows Noninvasive Quantification of LAG-3 Expression by Tumor-Infiltrating Leukocytes and Predicts Response of Immune Checkpoint Blockade

et al. 2021

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Recent advances in the field of immune-oncology led to the discovery of next-generation immune checkpoints (ICPs). Lymphocyte activation gene-3 (LAG-3), being the most widely studied amongst them, is being explored as a target for the treatment of cancer patients. Several antagonistic anti-LAG-3 antibodies are being developed and are prime candidates for clinical application. Furthermore, validated therapies targeting CTLA-4, PD-1 or PD-L1 showed that only subsets of patients respond. This finding highlights the need for better tools for patient selection and monitoring. The potential of molecular imaging to detect ICPs noninvasively in cancer is supported by several (pre)clinical studies. Here, we report on a nanobody to evaluate whole-body LAG-3 expression in various syngeneic mouse cancer models using nuclear imaging. The radiolabeled nanobody detected LAG-3 expression on tumor-infiltrating lymphocytes (TILs) as soon as 1 hour after injection in MC38, MO4 and TC-1 cancer models. The nanobody tracer visualized a compensatory upregulation of LAG-3 on TILs in MC38 tumors of mice treated with PD-1 blocking antibodies. When PD-1 blockade was combined with LAG-3 blockade, a synergistic effect on tumor growth delay was observed. These findings consolidate LAG-3 as a next-generation ICP and support the use of nanobodies as tools to noninvasively monitor the dynamic evolution of LAG-3 expression by TILs, which could be exploited to predict therapy outcome.

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Section: Discussionmentioning

confidence: 99%

Single-Domain Antibody Nuclear Imaging Allows Noninvasive Quantification of LAG-3 Expression by Tumor-Infiltrating Leukocytes and Predicts Response of Immune Checkpoint Blockade

et al. 2021

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“…PD-L1-targeting antibody fragments have recently been developed and used to generate high-contrast images of tumors with varying levels of PD-L1 expression [ 92 , 93 , 94 ]. Four high-affinity anti-PD-L1 nanobodies were radiolabeled with 99m Tc, and evaluated for preclinical SPECT/CT imaging of PD-L1 in syngeneic mice [ 92 ].…”

Section: Nanobodies As a Tool For Imaging Cancermentioning

confidence: 99%

Nanobodies for Medical Imaging: About Ready for Prime Time?

et al. 2021

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Recent advances in medical treatments have been revolutionary in shaping the management and treatment landscape of patients, notably cancer patients. Over the last decade, patients with diverse forms of locally advanced or metastatic cancer, such as melanoma, lung cancers, and many blood-borne malignancies, have seen their life expectancies increasing significantly. Notwithstanding these encouraging results, the present-day struggle with these treatments concerns patients who remain largely unresponsive, as well as those who experience severely toxic side effects. Gaining deeper insight into the cellular and molecular mechanisms underlying these variable responses will bring us closer to developing more effective therapeutics. To assess these mechanisms, non-invasive imaging techniques provide valuable whole-body information with precise targeting. An example of such is immuno-PET (Positron Emission Tomography), which employs radiolabeled antibodies to detect specific molecules of interest. Nanobodies, as the smallest derived antibody fragments, boast ideal characteristics for this purpose and have thus been used extensively in preclinical models and, more recently, in clinical early-stage studies as well. Their merit stems from their high affinity and specificity towards a target, among other factors. Furthermore, their small size (~14 kDa) allows them to easily disperse through the bloodstream and reach tissues in a reliable and uniform manner. In this review, we will discuss the powerful imaging potential of nanobodies, primarily through the lens of imaging malignant tumors but also touching upon their capability to image a broader variety of nonmalignant diseases.

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“…Due to the outstanding features, such as fast blood clearance, deep tissue penetration, and high a nity, sdAbs are identi ed as ideal candidates for nuclear medicine applications [16,17]. Several studies have demonstrated the safety and feasibility of radiolabeled sdAbs for cancer diagnosis and treatment [18][19][20][21][22][23][24][25][26]. In our previous study, we reported a 99m Tc-labeled antiprogrammed death ligand-1 (PD-L1) sdAb as a SPECT/CT tracer for PD-L1 expression in non-small cell lung cancer (NSCLC) [26].…”

Section: Introductionmentioning

confidence: 99%

First-in-human Study of a 99mTc-Labeled Single-Domain Antibody for SPECT/CT Assessment of HER2 Expression in Breast Cancer

Zhao

Liu

Xing

et al. 2021

Preprint

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Background: Accurate determination of human epidermal growth factor receptor 2 (HER2) expression is essential for HER2-targeted therapy. HER2 expression in a complex environment, such as in a heterogenous tumor, makes precise assessment difficult using current methods. Therefore, we developed a novel 99mTc-labeled anti-HER2-single domain antibody (99mTc-NM-02) as a molecular imaging tracer for non-invasive detection of HER2 expression and investigated its safety, radiation dosimetry, biodistribution, and tumor-targeting potential in breast cancer patients.Methods: A lead compound (NM-02) was screened from a library of hexahistidine-tagged anti-HER2-single domain antibodies and labeled with 99mTc for the preparation of 99mTc-NM-02 tracer. Ten women with breast cancer were administered 99mTc-NM-02 at a mean dose of 458 ± 37 MBq (406−510 MBq), corresponding to 100 μg of NM-02. Whole-body and local SPECT/CT images were acquired at 1 and 2 h post-administration to investigate the tumor-targeting potential in primary and metastatic lesions. Additional images were acquired at 10 min, 3 h, and 24 h in three patients to calculate radiation dosimetry. Physical evaluation and blood analysis were performed for safety assessment.Results: No drug-related adverse reactions occurred. The tracer mainly accumulated in the kidneys and liver with mild uptake in the spleen, intestines, and thyroid, but only background levels were observed in other organs where primary tumors and metastases typically occurred. The mean effective dose was 6.56 × 10−3 mSv/MBq, and tracer uptake was visually observed in primary tumors and metastases. Owing to the fast clearance of the tracer, we were able to sufficiently discern uptake over normal background in both primary lesions and metastases within 2 h after injection. A maximal standard uptake value of 1.5 could be a reasonable cutoff for determining HER2 positivity using SPECT/CT imaging.Conclusions: Our 99mTc-NM-02 tracer can be safely used for imaging in breast cancer patients with reasonable radiation doses, favorable biodistribution and imaging characteristics. 99mTc-NM-02 SPECT imaging may provide an accurate and non-invasive method to detect HER2 status in breast cancer patients.Trial registration: ClinicalTrials.gov, NCT04040686. Registered 30 July 2019. https://clinicaltrials.gov/ct2/show/NCT04040686.

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Anti-Human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation

Cited by 53 publications

References 32 publications

Single-Domain Antibody Nuclear Imaging Allows Noninvasive Quantification of LAG-3 Expression by Tumor-Infiltrating Leukocytes and Predicts Response of Immune Checkpoint Blockade

Single-Domain Antibody Nuclear Imaging Allows Noninvasive Quantification of LAG-3 Expression by Tumor-Infiltrating Leukocytes and Predicts Response of Immune Checkpoint Blockade

Nanobodies for Medical Imaging: About Ready for Prime Time?

First-in-human Study of a 99mTc-Labeled Single-Domain Antibody for SPECT/CT Assessment of HER2 Expression in Breast Cancer

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