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Molecular Imaging Using Nanobodies

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Molecular Imaging Using Nanobodies Molecular imaging using Nanobodies Tony Lahoutte, MD, PhD Feb 28th 2014 Wetenschappelijke Prijs prof. Roger Van Geen 1. Introduction Molecular imaging using Nanobodies started as a post-doctoral research topic in 2007 at the In vivo Cellular and Molecular Imaging (ICMI) laboratory of the Vrije Universiteit Brussel (VUB) directed by Tony Lahoutte. The idea of combining Nanobody technology with radionuclides to form radiotracers for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging originated during an interdisciplinary meeting between the nuclear medicine team of the VUB University Hospital (UZ Brussel - prof. Axel Bossuyt, Tony Lahoutte and Vicky Caveliers) and the VUB research group Cellular and Molecular Immunology (prof. De Baetselier, prof. Serge Muyldermans). Since then this combined technology has been investigated extensively in vitro and in vivo in preclinical models to refine the methodology and explore potential applications for both basic and clinical research. In 2011, the first clinical translation of radiolabeled Nanobodies was initiated and a Phase I clinical trial in breast cancer patients is currently ongoing at the department of Nuclear Medicine of UZ Brussel. This memorandum gives an overview of the Nanobody imaging technology and a description of the different applications that we investigated in the last 5 years. 2. Molecular imaging & Nanobodies 2.1 Molecular imaging Molecular imaging is aimed at the study of molecular and cellular events in intact living subjects. It has the unique advantage that the biology of health and disease can be studied non-invasively in its natural environment, offering new insights and opportunities for discovery. Nuclear imaging is at present the most sensitive and accurate method for molecular imaging. It requires the administration of a targeting probe labeled with a radioisotope. This radiolabeled probe or ‘tracer’ then distributes throughout the body, interacts with a specific molecular target and remains onsite while the unbound tracer is eliminated from the body. The most widely used tracer is 18F-Fluorodeoxyglucose or 18F-FDG in combination with PET imaging. 18F-FDG is intensely accumulated in sites with increased glucose metabolism and therefore used for the sensitive detection of cancer. In order to image a more specific marker of cancer it is possible to target antigens expressed on the cell membrane. A radiolabeled version of a ligand of the receptor has been extensively investigated in the last few decades. The use of radiolabeled antibodies for ‘immuno-imaging’ of cancer has received a lot attention in recent years and several radiolabeled conventional antibodies are currently used in clinical trials. The main limitation of this method is that it requires several days before a high contrasted image can be obtained due to the prolonged blood retention of intact antibodies. Imaging at several days after 124 injection requires a radiolabeling with isotopes with a long half-life such as I (t 1/2: 100,3h) and 89 Zr (t1/2:78,4h) resulting in a relatively high radiation dose per scan (20-40 mSv). As a result research has been focused on the use of radiolabeled fragments of immunoglobulins that are more rapidly cleared from the circulation. In our research we investigate Nanobodies that are the smallest possible functional fragments that are derived from antibodies. 2.2. Nanobodies Nanobodies are recombinant proteins that are derived from a particular type of antibodies that exist in the blood of camelids (llama, alpaca, vicuna, guanaco, camel and dromedary). In contrast to conventional antibodies that exist in all mammals (including human beings), the camelid 'heavy-chain antibodies' (HCAbs) lack a light chain (the green domains in the figure below). So, while conventional antibodies bind to foreign structures (the 'antigen') through the assembly of the variable domain of the heavy chain (VH) and that of the light chain (VL), the camelid HCAbs bind to antigen with a single domain called the VHH. This VHH (also called 'nanobody') can be easily produced in bacteria or yeast in large quantities, is very stable and binds to the antigen with high affinities and specificities. Also, Nanobodies are encoded by small DNA fragments and can be manipulated by genetic engineering in multiple formats and fusions. Since they are very small, Nanobodies efficiently penetrate into dense tissues. When they encounter antigen, Nanobodies get trapped, while unbound Nanobody is rapidly removed from the body through filtration by the renal system. As a result, radiolabeled Nanobodies generate very high specific contrast at the targeted site as early as 1 hour after administration. This allows the use of short-lived isotopes such as 68Ga or 18F and a more favorable dosimetry (2-4 mSv per scan) Figure 1. Comparison of conventional IgG antibody (left) and a Camelid heavy-chain-only nanobody (middle). The VHH fragment represents a Nanobody. Related references: Immuno-imaging using Nanobodies. Vaneycken I, D'huyvetter M, Hernot S, De Vos J, Xavier C, Devoogdt N, Caveliers V, Lahoutte T. Curr Opin Biotechnol. 2011 Dec;22(6):877-81 Molecular imaging using Nanobodies: a case study. Devoogdt N, Xavier C, Hernot S, Vaneycken I, D'Huyvetter M, De Vos J, Massa S, De Baetselier P, Caveliers V, Lahoutte T. Methods Mol Biol. 2012;911:559-67 Camelid single-domain antibody-fragment engineering for (pre)clinical in vivo molecular imaging applications: adjusting the bullet to its target. De Vos J, Devoogdt N, Lahoutte T, Muyldermans S. Expert Opin Biol Ther. 2013 May 16 3. Aim of the research The research focused on Molecular imaging using Nanobodies presented here is aimed at the development of new PET tracers for molecular imaging in oncology, inflammatory and cardiovascular diseases. Our major goal is to translate our lab findings into innovative clinical applications for diagnostic PET imaging. However, we also conduct more basic science investigations at our preclinical imaging facilities in order to identify the ideal conditions and formats for nanobodies as probes for molecular imaging. A recently added objective of our studies is to explore the feasibility of radionuclide therapy using the same Nanobody technology. This Nanobody research is embedded in a larger research theme that also includes the development of optical imaging tracers and detectors for image guided surgery. These applications are non-radioactive and beyond the scope of the current proposal. 4. Nanobody applications 4.1 Molecular imaging of cancer Our first research projects were aimed to develop nanobody-tracers for imaging of membrane antigens on cancer cells. Examples of successful projects include those targeting HER2, EGFR and CEA for breast, lung and colon cancer, respectively, and will be described hereunder. We are currently expanding our list of oncology tracers in collaboration with strategically-chosen academic and industrial partners. Targeted oncology biomarkers in the pipeline include CD20 for lymphomas, PSMA for prostate cancer and paraproteins for multiple myeloma. The choice to perform extensive preclinical imaging of cancer biomarkers is mostly based on its clinical relevance: all selected targets on the respective cancer cells have either prognostic value, can stratify patients eligible for receptor-targeted therapies and/or are suitable for nanobody- coupled radionuclide therapy. 4.1.1 Imaging Epidermal Growth Factor Receptor expression Epidermal Growth Factor Receptor (EGFR) is a membrane receptor of the Epithelial Growth Factor family and a prognostic biomarker for many cancer types. It is targeted by therapeutic antibodies such as Erbitux and by chemical tyrokinase inhibitors such as erlotinib. Anti-EGFR Nanobodies were evaluated as tracers for imaging of EGFR-positive xenografted tumors in mice. In a first hallmark study we showed the potential of the anti-EGFR nanobody 7C12 to target specifically the EGFR in cancer in vivo and demonstrated its applicability for fast non-invasive molecular imaging: 99mTc-labeled Nanobodies were cleared very fast out of blood and non-target organs, and accumulated in A431 EGFR-positive tumors but not in EGFR-negative R1M tumors with high tumor-to-organ ratios (Figure 2). This allowed us to visualize tumors with high contrast on SPECT/CT images within one hour after injection. Comparing two Nanobodies (7C12 and 7D12) that differ only in a few amino acids we showed that these small modifications can result in measurable differences in the general biodistribution and tumor targeting. In a next study we demonstrated that the anti-EGFR nanobody was useful to monitor tumor regression when mice were under therapy with erlotinib. Figure 2. Transverse, coronal, and sagittal views of fused pinhole SPECT and micro-CT images of mice bearing A431 and R1M xenografts. A431 (A) and R1M (C) tumors injected with 99mTc- 7C12. A431 (B) and R1M (D) tumors injected with 99mTc-7D12. Images were acquired at 1 h after injection. NIH white color scale is used, and images are equally scaled down to 10% relative to maximum activity in image. Related references: Correlation between epidermal growth factor receptor-specific nanobody uptake and tumor burden: a tool for noninvasive monitoring of tumor response to therapy. Gainkam LO, Keyaerts M, Caveliers V, Devoogdt N, Vanhove C, Van Grunsven L, Muyldermans S, Lahoutte T. Mol Imaging Biol. 2011 Oct;13(5):940-8. Comparison of the biodistribution and tumor targeting of two 99mTc-labeled anti-EGFR Nanobodies in mice, using pinhole SPECT/micro-CT. Gainkam LO, Huang L, Caveliers V, Keyaerts M, Hernot S, Vaneycken I, Vanhove C, Revets H, De Baetselier P, Lahoutte T. J Nucl Med. 2008 May;49(5):788-95 SPECT imaging with 99mTc-labeled EGFR-specific nanobody for in vivo monitoring of EGFR expression. Huang L, Gainkam LO, Caveliers V, Vanhove C, Keyaerts M, De Baetselier P, Bossuyt a, Revets H, Lahoutte T. Mol Imaging Biol. 2008 May-Jun;10(3):167-75 Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Gainkam LO, Caveliers V, Devoogdt N, Vanhove C, Xavier C, Boerman O, Muyldermans S, Bossuyt A, Lahoutte T.
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