Novel Recombinant Traceable C-Met Antagonist-Avimer Antibody Mimetic Obtained by Bacterial Expression Analysis
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Affibody Molecules for Epidermal Growth Factor Receptor Targeting
Journal of Nuclear Medicine, published on January 21, 2009 as doi:10.2967/jnumed.108.055525 Affibody Molecules for Epidermal Growth Factor Receptor Targeting In Vivo: Aspects of Dimerization and Labeling Chemistry Vladimir Tolmachev1-3, Mikaela Friedman4, Mattias Sandstrom¨ 5, Tove L.J. Eriksson2, Daniel Rosik2, Monika Hodik1, Stefan Sta˚hl4, Fredrik Y. Frejd1,2, and Anna Orlova1,2 1Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; 2Affibody AB, Bromma, Sweden; 3Department of Medical Sciences, Nuclear Medicine, Uppsala University, Uppsala, Sweden; 4Division of Molecular Biotechnology, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden; and 5Section of Hospital Physics, Department of Oncology, Uppsala University Hospital, Uppsala, Sweden Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecu- he epidermal growth factor receptor (EGFR; other lar imaging may provide diagnostic information influencing pa- T designations are HER1 and ErbB-1) is a transmembrane tient management. The aim of this study was to evaluate a tyrosine kinase receptor that regulates cell proliferation, novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a motility, and suppression of apoptosis (1). Overexpression suitable tracer format (dimer or monomer) and optimal label. of EGFR is documented in several malignant tumors, such Methods: An EGFR-specific Affibody molecule, ZEGFR:1907, as carcinomas of the breast, urinary bladder, and lung, and 111 and its dimeric form, (ZEGFR:1907)2, were labeled with In using is associated with poor prognosis (2). A high level of EGFR 125 benzyl-diethylenetriaminepentaacetic acid and with I using expression could provide malignant cells with an advantage p-iodobenzoate. -
Strategies and Challenges for the Next Generation of Therapeutic Antibodies
FOCUS ON THERAPEUTIC ANTIBODIES PERSPECTIVES ‘validated targets’, either because prior anti- TIMELINE bodies have clearly shown proof of activity in humans (first-generation approved anti- Strategies and challenges for the bodies on the market for clinically validated targets) or because a vast literature exists next generation of therapeutic on the importance of these targets for the disease mechanism in both in vitro and in vivo pharmacological models (experi- antibodies mental validation; although this does not necessarily equate to clinical validation). Alain Beck, Thierry Wurch, Christian Bailly and Nathalie Corvaia Basically, the strategy consists of develop- ing new generations of antibodies specific Abstract | Antibodies and related products are the fastest growing class of for the same antigens but targeting other therapeutic agents. By analysing the regulatory approvals of IgG-based epitopes and/or triggering different mecha- biotherapeutic agents in the past 10 years, we can gain insights into the successful nisms of action (second- or third-generation strategies used by pharmaceutical companies so far to bring innovative drugs to antibodies, as discussed below) or even the market. Many challenges will have to be faced in the next decade to bring specific for the same epitopes but with only one improved property (‘me better’ antibod- more efficient and affordable antibody-based drugs to the clinic. Here, we ies). This validated approach has a high discuss strategies to select the best therapeutic antigen targets, to optimize the probability of success, but there are many structure of IgG antibodies and to design related or new structures with groups working on this class of target pro- additional functions. -
Article in Press
G Model MIMM-4561; No. of Pages 12 ARTICLE IN PRESS Molecular Immunology xxx (2015) xxx–xxx Contents lists available at ScienceDirect Molecular Immunology j ournal homepage: www.elsevier.com/locate/molimm Review Alternative molecular formats and therapeutic applications for ଝ bispecific antibodies ∗ Christoph Spiess, Qianting Zhai, Paul J. Carter Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA a r t i c l e i n f o a b s t r a c t Article history: Bispecific antibodies are on the cusp of coming of age as therapeutics more than half a century after they Received 28 November 2014 ® were first described. Two bispecific antibodies, catumaxomab (Removab , anti-EpCAM × anti-CD3) and Received in revised form ® blinatumomab (Blincyto , anti-CD19 × anti-CD3) are approved for therapy, and >30 additional bispecific 30 December 2014 antibodies are currently in clinical development. Many of these investigational bispecific antibody drugs Accepted 2 January 2015 are designed to retarget T cells to kill tumor cells, whereas most others are intended to interact with two Available online xxx different disease mediators such as cell surface receptors, soluble ligands and other proteins. The modular architecture of antibodies has been exploited to create more than 60 different bispecific antibody formats. Keywords: These formats vary in many ways including their molecular weight, number of antigen-binding sites, Bispecific antibodies spatial relationship between different binding sites, valency for each antigen, ability to support secondary Antibody engineering Antibody therapeutics immune functions and pharmacokinetic half-life. These diverse formats provide great opportunity to tailor the design of bispecific antibodies to match the proposed mechanisms of action and the intended clinical application. -
WO 2014/152006 A2 25 September 2014 (25.09.2014) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/152006 A2 25 September 2014 (25.09.2014) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 39/395 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 14/026804 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 13 March 2014 (13.03.2014) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/791,953 15 March 2013 (15.03.2013) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: INTRINSIC LIFESCIENCES, LLC UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/US]; 505 Coast Boulevard South, Suite 408, La Jolla, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, California 92037 (US). -
WO 2018/144999 Al 09 August 2018 (09.08.2018) W ! P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/144999 Al 09 August 2018 (09.08.2018) W ! P O PCT (51) International Patent Classification: Lennart; c/o Orionis Biosciences NV, Rijvisschestraat 120, A61K 38/00 (2006.01) C07K 14/555 (2006.01) Zwijnaarde, B-9052 (BE). TAVERNIER, Jan; c/o Orionis A61K 38/21 (2006.01) C12N 15/09 (2006.01) Biosciences NV, Rijvisschestraat 120, Zwijnaarde, B-9052 C07K 14/52 (2006.01) (BE). (21) International Application Number: (74) Agent: ALTIERI, Stephen, L. et al; Morgan, Lewis & PCT/US2018/016857 Bockius LLP, 1111 Pennsylvania Avenue, NW, Washing ton, D.C. 20004 (US). (22) International Filing Date: 05 February 2018 (05.02.2018) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (26) Publication Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (30) Priority Data: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 62/454,992 06 February 2017 (06.02.2017) US KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (71) Applicants: ORIONIS BIOSCIENCES, INC. [US/US]; MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 275 Grove Street, Newton, MA 02466 (US). -
EURL ECVAM Recommendation on Non-Animal-Derived Antibodies
EURL ECVAM Recommendation on Non-Animal-Derived Antibodies EUR 30185 EN Joint Research Centre This publication is a Science for Policy report by the Joint Research Centre (JRC), the European Commission’s science and knowledge service. It aims to provide evidence-based scientific support to the European policymaking process. The scientific output expressed does not imply a policy position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of this publication. For information on the methodology and quality underlying the data used in this publication for which the source is neither Eurostat nor other Commission services, users should contact the referenced source. EURL ECVAM Recommendations The aim of a EURL ECVAM Recommendation is to provide the views of the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) on the scientific validity of alternative test methods, to advise on possible applications and implications, and to suggest follow-up activities to promote alternative methods and address knowledge gaps. During the development of its Recommendation, EURL ECVAM typically mandates the EURL ECVAM Scientific Advisory Committee (ESAC) to carry out an independent scientific peer review which is communicated as an ESAC Opinion and Working Group report. In addition, EURL ECVAM consults with other Commission services, EURL ECVAM’s advisory body for Preliminary Assessment of Regulatory Relevance (PARERE), the EURL ECVAM Stakeholder Forum (ESTAF) and with partner organisations of the International Collaboration on Alternative Test Methods (ICATM). Contact information European Commission, Joint Research Centre (JRC), Chemical Safety and Alternative Methods Unit (F3) Address: via E. -
Generation of Novel Intracellular Binding Reagents Based on the Human Γb-Crystallin Scaffold
Generation of novel intracellular binding reagents based on the human γB-crystallin scaffold Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Naturwissenschaftlichen Fakultät I-Biowissenschaften der Martin-Luther-Universität Halle-Wittenberg Institut für Biochemie und Biotechnologie von Ewa Mirecka geboren am 17. Dezember 1976 in Gdynia, Polen Table of contents Table of contents 1. INTRODUCTION.........................................................................................................1 1.1 Monoclonal antibodies as a biomolecular scaffold..........................................................1 1.2 Binding molecules derived from non-immunoglobulin scaffolds.....................................3 1.2.1 Alternative protein scaffolds – general considerations............................................................ 3 1.2.2 Application of alternative binding molecules ........................................................................... 6 1.3 Affilin – novel binding molecules based on the human γB-crystallin scaffold................... 6 1.3.1 Human γB-crystallin as a molecular scaffold........................................................................... 6 1.3.2 Generation of a human γB-crystallin library and selection of first-generation Affilin molecules ................................................................................................................................ 8 1.4 Selection of binding proteins by phage display ................................................................... -
An Affibody Molecule Is Actively Transported Into the Cerebrospinal
International Journal of Molecular Sciences Article An Affibody Molecule Is Actively Transported into the Cerebrospinal Fluid via Binding to the Transferrin Receptor Sebastian W. Meister , Linnea C. Hjelm , Melanie Dannemeyer, Hanna Tegel, Hanna Lindberg, Stefan Ståhl and John Löfblom * Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Centre, SE-106 91 Stockholm, Sweden; [email protected] (S.W.M.); [email protected] (L.C.H.); [email protected] (M.D.); [email protected] (H.T.); [email protected] (H.L.); [email protected] (S.S.) * Correspondence: [email protected]; Tel.: +46-8-790-9659 Received: 6 March 2020; Accepted: 22 April 2020; Published: 23 April 2020 Abstract: The use of biotherapeutics for the treatment of diseases of the central nervous system (CNS) is typically impeded by insufficient transport across the blood–brain barrier. Here, we investigate a strategy to potentially increase the uptake into the CNS of an affibody molecule (ZSYM73) via binding to the transferrin receptor (TfR). ZSYM73 binds monomeric amyloid beta, a peptide involved in Alzheimer’s disease pathogenesis, with subnanomolar affinity. We generated a tri-specific fusion protein by genetically linking a single-chain variable fragment of the TfR-binding antibody 8D3 and an albumin-binding domain to the affibody molecule ZSYM73. Simultaneous tri-specific target engagement was confirmed in a biosensor experiment and the affinity for murine TfR was determined to 5 nM. Blockable binding to TfR on endothelial cells was demonstrated using flow cytometry and in a preclinical study we observed increased uptake of the tri-specific fusion protein into the cerebrospinal fluid 24 h after injection. -
WO 2019/068007 Al Figure 2
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/068007 Al 04 April 2019 (04.04.2019) W 1P O PCT (51) International Patent Classification: (72) Inventors; and C12N 15/10 (2006.01) C07K 16/28 (2006.01) (71) Applicants: GROSS, Gideon [EVIL]; IE-1-5 Address C12N 5/10 (2006.0 1) C12Q 1/6809 (20 18.0 1) M.P. Korazim, 1292200 Moshav Almagor (IL). GIBSON, C07K 14/705 (2006.01) A61P 35/00 (2006.01) Will [US/US]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., C07K 14/725 (2006.01) P.O. Box 4044, 7403635 Ness Ziona (TL). DAHARY, Dvir [EilL]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., P.O. (21) International Application Number: Box 4044, 7403635 Ness Ziona (IL). BEIMAN, Merav PCT/US2018/053583 [EilL]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., P.O. (22) International Filing Date: Box 4044, 7403635 Ness Ziona (E.). 28 September 2018 (28.09.2018) (74) Agent: MACDOUGALL, Christina, A. et al; Morgan, (25) Filing Language: English Lewis & Bockius LLP, One Market, Spear Tower, SanFran- cisco, CA 94105 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/564,454 28 September 2017 (28.09.2017) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/649,429 28 March 2018 (28.03.2018) US CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (71) Applicant: IMMP ACT-BIO LTD. -
PET Imaging of HER2-Positive Tumors with Cu-64-Labeled
Mol Imaging Biol (2019) 21:907Y916 DOI: 10.1007/s11307-018-01310-5 * World Molecular Imaging Society, 2019 Published Online: 7 January 2019 RESEARCH ARTICLE PET Imaging of HER2-Positive Tumors with Cu-64-Labeled Affibody Molecules Shibo Qi,1,2 Susan Hoppmann,2 Yingding Xu,2 Zhen Cheng 2 1School of Environmental and Chemical Engineering, Tianjin Polytechnic University, Tianjin, 300387, China 2Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA, 94305-5344, USA Abstract Purpose: Previous studies has demonstrated the utility of human epidermal growth factor receptor type 2 (HER2) as an attractive target for cancer molecular imaging and therapy. An affibody protein with strong binding affinity for HER2, ZHER2:342, has been reported. Various methods of chelator conjugation for radiolabeling HER2 affibody molecules have been described in the literature including N-terminal conjugation, C-terminal conjugation, and other methods. Cu-64 has recently been extensively evaluated due to its half-life, decay properties, and availability. Our goal was to optimize the radiolabeling method of this affibody molecule with Cu- 64, and translate a positron emission tomography (PET) probe with the best in vivo performance to clinical PET imaging of HER2-positive cancers. Procedures: In our study, three anti-HER2 affibody proteins-based PET probes were prepared, and their in vivo performance was evaluated in mice bearing HER2-positive subcutaneous 39 SKOV3 tumors. The affibody analogues, Ac-Cys-ZHER2:342,Ac-ZHER2:342(Cys ), and Ac- ZHER2:342-Cys, were synthesized using the solid phase peptide synthesis method. -
Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology
FOCUS ON MOLECULAR IMAGING Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology Ahmet Krasniqi1, Matthias D’Huyvetter1, Nick Devoogdt1, Fredrik Y. Frejd2,3, Jens S¨orensen4,5, Anna Orlova6, Marleen Keyaerts*1,7, and Vladimir Tolmachev*3 1In Vivo Cellular and Molecular Imaging Laboratory (ICMI), VUB, Brussels, Belgium; 2Affibody AB, Solna, Sweden; 3Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 4Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 5Medical Imaging Centre, Uppsala University Hospital, Uppsala, Sweden; 6Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden; and 7Nuclear Medicine Department, UZ Brussel, Brussels, Belgium major disadvantage is the long blood circulation time, with half-lives of up to 28 d, requiring delayed scanning time Imaging of expression of therapeutic targets may enable points typically between 4 and 6 d (Fig. 1A). Even at that stratification of patients for targeted treatments. The use of small radiolabeled probes based on the heavy-chain variable time, appreciable quantities of the tracer remain in the blood, region of heavy-chain–only immunoglobulins or nonimmunoglo- resulting in low sensitivity due to high background uptake and bulin scaffolds permits rapid localization of radiotracers in low specificity due to an enhanced permeability and retention tumors and rapid clearance from normal tissues. This makes effect, especially for targets with a low expression level. high-contrast imaging possible on the day of injection. This To overcome the slow clearance and extravasation, mAbs mini review focuses on small proteins for radionuclide-based have been engineered to smaller fragments such as antigen- imaging that would allow same-day imaging, with the emphasis on clinical applications and promising preclinical developments binding, variable, and single-chain variable fragments; within the field of oncology. -
Engineering Bispecific Antibodies for Targeted Delivery of Cytotoxin- Loaded Nanoparticles to Tumour Cells
Engineering bispecific antibodies for targeted delivery of cytotoxin- loaded nanoparticles to tumour cells by Karin Taylor Bachelor of Science (Genetics) Bachelor of Science Honours (Genetics) Graduate Certificate in Business A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 The Australian Institute for Bioengineering and Nanotechnology (AIBN) Abstract First-line cancer treatments, such as surgical removal of tumours, are necessary but highly invasive and can only be of therapeutic benefit if the cancer has not yet spread to other organs. Chemotherapy and radiotherapy can help to slow the spread of cancer, but the systemic exposure leads to cumulative and cytotoxic effects, which leave the patient immune-compromised and susceptible to organ failure. This highlights the need to develop targeted therapies capable of delivering such drugs directly to the cancer cells, to overcome drug resistance and limit the cytotoxic effects associated with chemotherapeutics. Monoclonal antibodies (mAbs) provide a means to target conjugated drugs or radio-labels while also having therapeutic benefits in their own right. Cancer cells are often characterised by the overexpression of particular cell surface biomarkers, and these biomarkers make ideal targets for delivery of drugs via specific mAbs. The epidermal growth factor receptor (EGFR) is a validated cell surface antigen that has been extensively evaluated in the literature. EGFR is associated with a number of different cancers including breast and colon, and anti-EGFR mAbs are approved for therapeutic use (e.g. panitumumab and cetuximab). Drug-conjugated anti-EGFR mAbs are also under pre- clinical and clinical evaluation. However significant challenges remain, as some cancers are refractive to mAb therapy due to pre-existing and acquired resistance to a given treatment, both mAb and drug related.