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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Z-doamin affibody specific to Taq DNA polymerase was generated through a combinatorial library of three-helix bundle. To further increase the affinity of affibody, a hierarchical library was generated by stochastic evaluation of 6 amino acids in one of helices that bind to Taq DNA polymerase. Affibody with a binding affinity of 30–50 nM was obtained for Taq DNA polymerase (Gunneriusson et al., 1999). Affibodies particular to proteins that are highly specific for different types of cancers are being developed to detect different malignancies. Affibody specific to HER2 has been engineered that showed binding affinity of 22 pmol/L to HER2 and hence can be used to detect the expression of HER2 in the cells using gamma camera (Orlova et al., 2006). Fluorescently labeled affibodies are being produced to function as biosensors. The triple-labeled affibody molecule has already been shown to detect unlabeled human IgG and IgA (Engfeldt et al., 2005). Affibody molecules are also being exploited in numerous biotechnological, pharmaceutical, and diagnostic applications which are discussed in detail in a review by Löfblom et al. and Nygren (Nygren, 2008; Lofblom et al., 2010).
Radioimmunodetection of Cancer: The Next Dimension
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
David M. Goldenberg, Robert M. Sharkey
Although the monovalent fragments and constructs have favorable clearance properties, they lack the avidity of multivalent molecules. Innovative strategies have been undertaken to restore the multivalency of an antibody to enhance tumor retention, while also engineering the molecule for rapid clearance. For example, deleting the CH2 sequence of an IgG results in a divalent construct of ~ 100 kDa that clears extraordinarily fast from the blood, resulting in high localization ratios within a short period (67). A number of new constructs, ranging from divalent diabodies, minibodies, (scFv)2-Fc, and other assorted constructs, are essentially composed of multiple scFvs tethered in different ways, as illustrated in Figure 1 (64,68–70). An entirely different type of antibody, an affibody, has been described recently that has some promising properties for imaging as well as therapy. An affibody is not based on immunoglobulin structures, but instead is a novel scaffold protein prepared from a mutated variant of the B-domain of the Staphylococcus aureus protein A, known as the Z-domain. This 6.5-kDa molecule has been the basis for preparing targeting agents to HER2/neu labeled with 99mTc, 111In, and even 177Lu for therapy (71–75). Tolmachev et al. (72) have also described an affibody-albumin-binding domain fusion protein that allows the affibody to bind to a patient’s own albumin on injection, which in turn favorably alters the pharmacokinetics and distribution properties of the labeled compound for improved imaging and therapy.
Izokibep: Preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis
Published in mAbs, 2023
Susanne Klint, Joachim Feldwisch, Lindvi Gudmundsdotter, Karin Dillner Bergstedt, Elin Gunneriusson, Ingmarie Höidén Guthenberg, Anders Wennborg, Andrew C. Nyborg, Amol P. Kamboj, Paul M. Peloso, David Bejker, Fredrik Y. Frejd
Collectively, data to date suggest that increased efficacy in treating IL-17-driven pathology may be achieved with a molecule that: 1) completely and selectively inhibits homodimeric IL-17A signaling, 2) has a relatively small size to allow increased tissue exposure, and 3) has favorable biodistribution properties with a long in vivo half-life, allowing preferential accumulation at sites of inflammation such as skin lesions. Affibody molecules represent a class of small, triple helical high-affinity protein domains that are approximately 6.5 kDa in size and well suited for therapeutic development.29,30 Affibody molecules are often engineered as a fusion protein with a small albumin-binding domain to extend plasma half-life and achieve better tissue penetration, including high drug exposure at sites of inflammation.30–35
A PDGFRB- and CD40-targeting bispecific AffiMab induces stroma-targeted immune cell activation
Published in mAbs, 2023
Alessandro Mega, Aman Mebrahtu, Gustav Aniander, Eva Ryer, Annette Sköld, Anna Sandegren, Eva Backström Rydin, Johan Rockberg, Arne Östman, Fredrik Y. Frejd
Affibody molecules are small (6.5 kDa) and very stable affinity proteins based on a three-helix bundle domain. Through combinatorial protein engineering, Affibody molecules can be selected with the ability to bind any given target.25 Their small size, lack of disulfide bonds and robustness of the molecules make them ideal tools for tumor targeting26 and as fusion partners with monoclonal antibodies (mAbs) to create multispecific antibody-based affinity proteins, denoted AffiMabs.27 Clinical utility of Affibody molecules has been demonstrated both for tumor targeting in patients with metastatic breast cancer,28 as well as for chronic treatment of inflammatory disorders with data of well-tolerated and efficacious treatment of patients with plaque psoriasis up to three years.29 An Affibody molecule is available for binding to PDGFRB, named ZPDGFRb_3,30 and has been shown in imaging studies to target PDGFRB-expressing remodeling tumor stroma in syngeneic tumors and in xenografts of glioma (U87) in vivo.30,31
Current strategies for the discovery and bioconjugation of smaller, targetable drug conjugates tailored for solid tumor therapy
Published in Expert Opinion on Drug Discovery, 2021
Mahendra P. Deonarain, Gokhan Yahioglu
Affibodies are a scaffold derived from the 6kDa Staphylococcus protein-A, Z-domain which can be manipulated and phage-displayed to generate high-affinity binders. These are being developed as therapeutics by clinical-stage biotech company Affibody AB (Sweeden) [66]. No commercial affibody-drug conjugates have been described, but conjugates have been published targeting HER2 (ZHER2891) with a vcMMAE payload (DAR1) with low nM potency [67]. Fc-fusions which were of higher affinity with a longer half-life had increased potency on SKBr3 cells in vitro (130 pM) [68]. More recently, the same affibody formats were coupled to the non-releasable DM1 payload (DAR1) resulting in higher in vitro potencies (270–470pM, comparable to the trastuzumab ADC) and significant in vivo efficacy. Five doses of 8.5 mg/kg, given weekly were needed to see well-tolerated, 20-day tumor growth delay of but no cures were seen in this first in vivo proof-of-principle of this scaffold format [69]. Conjugates radiolabelled with technicium-99 showed slightly higher tumor uptake at 4 h but higher blood and normal organ uptake. The same affibody was also conjugated with a photosensitizer payload (pyropheophorbide-a, DAR1) with ~20 nM IC50 potency. Well-tolerated cures were seen with a single injection of 20 nMol of conjugate (~0.2 mg dose or 8 mg/kg) upon laser illumination with the rapid clearance being optimal to allow photo-activation without skin toxicity [70].