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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another fragment approach is the diabodies (Db) format. Diabodies are bivalent molecules produced from scFvs, with the VH and VL fragments usually connected through a short five-residue linker. The main purpose for the development of diabodies was to target effector tumor cells (i.e., EGFR). There are issues associated with the production of diabodies; for example, nonfunctional homodimers can result from the incorrect pairing of variable domains. In order to address this problem, disulphide bridges have been introduced between the variable domains to improve stability. There are multiple diabody formats in development, one example being the Dual-Affinity Re-Targeting (DART) proteins which consist of a covalent union of the heavy chain of one arm of an antibody combined with the light chain of another. DARTs are larger than BiTEs but have better serum stability presumably due to the additional stabilization of the molecule through the inserted disulphide bridges. Other examples include the tandem diabodies (TandAbs) which are potent recruiters of immune effector cells to kill tumor cells, and a number of these are currently undergoing clinical trials for the treatment of hematological malignancies.
Nanocarriers as an Emerging Platform for Cancer Therapy
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, Robert Langer
Although using genomics and proteomics technology to choose appropriate targets is an active area of research, to date no clinically effective targets have been identified. Creating new technologies to enhance selectivity and targeting efficacy with existing targets seem more promising. For example, fusion proteins can be created by combining two or more genes to produce a new protein with desired properties. Antibodies can be engineered so they bind to their target with high affinity, and using molecular biology techniques, it is possible to design protein-based ligand mimetics based on the structure of a receptor. Dimerization of proteins or peptides can increase ligand affinity through divalency—two simultaneous binding events, usually involving concurrent binding of a protein or a peptide to the two Fc domains of an antibody (Fig. 2.2b). For example, dimerization of a low-affinity scFv (also known as diabody) against the ErbB2, led to enhanced tumour localization in a mouse tumour model [37].
Molecular Farming Antibodies in Plants: From Antibody Engineering to Antibody Production
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 2002
Rainer Fischer, Ricarda Finnern, Olga Artsaenko, Stefan Schillberg
The rAb fragments most commonly used in research and therapy are single chain Fv antibody fragments (scFvs) and Fragment antigen binding (Fab) fragments. In Fab based phage-display libraries, DNA encoding the heavy chain variable (VH) domain and the first domain of the heavy chain constant domain is inserted into a phage or phagemid vector in tandem with the light chain variable (VL) and constant domain. In bacteria, the two polypeptide chains are produced separately and assemble spontaneously in the bacterial periplasm [18-21]. In scFv-based phage-display libraries, the VH and VL domains are joined by a flexible linker into a single polypeptide chain. This stabilizes the protein and ensures the equal expression of both regions in heterologous organisms. While most scFvs are monomeric, some can form higher molecular weight species, including dimers and trimers, which can complicate selection and characterization [22]. This tendency to dimerize has been exploited to create diabodies [23-25] and triabodies [25, 26]. Diabodies may be either bivalent molecules with enhanced avidity, or bispecific molecules with the ability to re-target immune effector functions, including complement fixation, antibody-dependent cell-mediated cytotoxicity and cytotoxic T-cell killing [27-33]. Diabody repertoires can also be displayed on phage and selected on antigen [34].
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
The advantages of antibody fragments over whole monoclonal antibodies, like rapid tumor accumulation and enhanced penetration are negated by their rapid overall clearance. PEGylation and half-life extension technologies like albumin-binding domains (ABD) are commonly used to alter and improve the PK profile of many biological proteins. This was clearly demonstrated with a diabody targeting the oncofetal antigen 5T4, where ABD fusion or conjugation of two PEG20K chains altered the half-life of the diabody from minutes to days [52]. A similar study was carried out with the diabody conjugated to a PBD warhead (DAR 2). This was either carried out with maleimide terminated payload at engineered cysteines on the ABD-diabody fusion or on dual-functionalized a 5T4 azido-diabody with the alkyne functionalized PBD drug linker followed by site-specific PEGylation at the engineered cysteines (Figure 1(f)). In an in vivo efficacy study, a clear link between PK and antitumour activity was observed with the ABD-diabody-PBD showing the best tumor growth suppression and tolerability compared to the PEG-diabody-PBD and diabody-PBD [52].
Expanding use of CD33-directed immunotherapy
Published in Expert Opinion on Biological Therapy, 2020
Data from an increasing number of studies support a pivotal role of MDSCs in the pathogenesis of many disorders. These include cancers where MDSCs are considered important contributors to immune suppression and evasion, tumor angiogenesis, drug resistance (including resistance to checkpoint inhibitor therapy, bispecific antibodies, and CAR-modified T cells), and tumor metastasis, but also infections and chronic inflammatory diseases [29–33]. Particularly for patients with cancer, this has raised interest in therapeutically targeting MDSCs, with a variety of approaches being currently explored [32,34,35]. The data summarized above with MDSCs from patients with AML and MDS suggest that CD33 might be a suitable target for MDSC therapy even beyond the treatment of CD33+ hematologic malignancies. In fact, based on the notion that the CD33/CD3 tandem diabody AMV564 targets AML- and MDS-associated MDSCs [12], a trial with this agent for adults with advanced solid tumors has been initiated (NCT04128423).
Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs)
Published in OncoImmunology, 2018
Ricarda M. Hoffmann, Ben G. T. Coumbe, Debra H. Josephs, Silvia Mele, Kristina M. Ilieva, Anthony Cheung, Andrew N. Tutt, James F. Spicer, David E. Thurston, Silvia Crescioli, Sophia N. Karagiannis
Despite the optimization of therapeutic antibodies and the availability of antibodies with higher affinity for the tumor than for normal tissues, the amount of antibody that reaches a tumor is only a small percentage of that administered (e.g., approximately 1–2%).1,78,79 For this reason the use of recombinant antibody fragments for ADC production has been evaluated. Antibody fragments such as diabodies are much smaller then IgGs (around 50 kDa versus 150 kDa) and thus have superior tissue penetration abilities. However, due to their smaller size and the lack of the Fc portion that usually binds to FcRn, diabodies are cleared much faster than whole IgG isotypes.80 A promising anti-CD30 diabody-drug conjugate has already demonstrated high anti-tumor activity,81 but the use of diabodies for ADC design needs further study and optimization with a view to striking a balance between optimum tissue penetration and low clearance rates.