China
Africa
Explore chapters and articles related to this topic
Science of biotechnology – Monoclonal antibody technology
Published in Ronald P. Evens, Biotechnology, 2020
An alternative mode of development for monoclonal antibodies is antibody “phage” display (APD), which has been used in 5 of the 86 mab molecules currently marketed (adalimumab, belimumab, necitumumab, ramucirumab, raxibacumab). In APD, mabs are fully developed in the test tube, based on the physical link between function (antigen binding of mabs) and information (mab genes) in nanoparticle phages (viruses that infect bacteria, such as Escherichia coli). The high antigen affinity and high specificity of mabs to their antigen allows APD to create the specific mab for the specific antigen of a disease. Four main elements are required, that is, (1) preparation of human antibody gene libraries containing millions of mab genes, (2) genetic engineering of bacteriophages to bind mabs [the antigen-binding fragment (Fab) or single-chain variable fragment (scFv) segments of a mab] and serve as probes to filter out mabs against desired antigen targets, (3) serial panning of the gene libraries with the bacteriophage-mab probes, (4) analysis of mab clones. Then, the manufacture of mabs by recombinant DNA methods can ensue. An advantage of this APD system is that the mabs are fully human. A limit to this set of procedures is the laborious nature of the process.
Precision
Published in Lawrence S. Chan, William C. Tang, Engineering-Medicine, 2019
In fact, this modified/activated T cells is like a “living drug” as they are indeed alive and serving as a drug. The most advanced ACT method is the “CAR T cell therapy”, where CAR is the abbreviation for “chimeric antigen receptor” (NIH 2018). The first successful report of using this technique, through which patient’s T cells are engineered to form a novel T cell receptor recognizing a tumor antigen, was by a NIH research group led by Dr. Rosenberg, resulting in complete eliminating a form of childhood leukemia (Kochenderfer et al. 2010). Due to such remarkable clinical results, two CAR T cell therapies were approved by FDA in 2017, one for childhood acute lymphoblastic leukemia and one for adult advanced lymphoma (NCI 2018b). To monitor long-term success and adverse effects, particularly due to the use of a non-pathogenic viral vector, lentivirus or retrovirus vector, in the engineering of the CAR, NIH has initiated a long-term follow-up study, starting on November 2, 2015, with estimated complete date on September 5, 2036 and 620 participating patients (NIH 2018). A Schematic representation of 3rd generation of engineered CAR (chimeric antigen receptor) of T cell is depicted in Fig. 2. CAR commonly is consisted of an ectodomain of single chain variable fragment of an antibody, a hinge and spacer segment, a transmembrane domain, and an internal signal domain (such as CD3). Costimulatory domains (such as CD28 and 4-1BB) have been added to the later generations of CARs to enhance the transgenic T cell expansion and longevity. The construction of the binding ectodomain with single chain variable fragment (scFv) of antibody has the advantage of bypassing the MHC restriction of T cells, thus allowing the direct activation of effector cells for killing cancer cells.
Detecting and Destroying Cancer Cells in More Than One Way with Noble Metals and Different Confinement Properties on the Nanoscale *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Erik C. Dreaden, Mostafa A. El-Sayed
While mild hyperthermic cancer treatments have been in clinical use since the early 1980s [22], laser photothermal therapy (or ablation) using plasmonic nanoparticles was first demonstrated in 2003 by locally injecting so-called gold nanoshells (silica-gold core-shell nanoparticles) directly into the tumor interstitium and later by the passive accumulation of systemically delivered nanoshells [23]. Our group [2] was the first to show that increasingly efficient [3] gold nanorods could be used as contrast agents for in vitro and in vivo near-infrared (NIR) laser photothermal therapy to achieve selective tumor cell ablation and resorption/remission in vivo (Fig. 1.3). In the latter, NIR-absorbing PEGylated gold nanorods were systemically or intratumorally administered in mice bearing head and neck tumor models (squamous cell carcinoma). Subsequent exposure of the nanoparticle-loaded tumors for just 10 min was found to result in upward of 20°C temperature increases at the tumor center, with minimal damage to surrounding tissues. Complete tumor resorption was observed in more than 50% of the group directly administered gold nanorods and 25% of those systemically administered at 2 weeks post-laser treatment [2]. Subsequent studies by our group [24] exploring active targeting of these nanorods by (i) a single-chain variable fragment (ScFv) peptide that recognizes the epidermal growth factor receptor (EGFR), (ii) an amino terminal fragment (ATF) peptide that recognizes the urokinase plasminogen activator receptor (uPAR), or (iii) a cyclic RGD peptide that recognizes the avb3 integrin receptor were also performed (hydrodynamic diameter 68–81 nm, zeta potential −5 to −25 mV). As expected, active targeting significantly improved the cellular accumulation of these nanoconjugates in vitro (A549 lung cancer cells). The blood half-life of PEGylated gold nanorods was reduced by 25%–48% upon co-conjugation with these active targeting ligands and the tumor accumulation (24 h) of ATF- and ScFV EGFR-targeted gold nanorods was enhanced ca. 67% and 46% relative to passively targeted PEGylated gold nanorods administered in mice models (Fig. 1.4). Surprisingly, the tumor accumulation of cyclic RGD-targeted gold nanorods was significantly diminished (ca. −57% relative to PEGylated gold nanorods), suggesting that laser photothermal therapy using this specific formulation may be best suited to intratumoral injection schemes. The use of gold nanocage [25] and hollow gold nanoparticles [26] as contrast agents in preclinical laser photothermal cancer therapy have also been subsequently explored by Xia and Li, respectively, and human pilot studies investigating the treatment of refractory and/or recurrent head and neck tumors using plasmonic laser photothermal therapy are currently ongoing [27].
Toward generalizable prediction of antibody thermostability using machine learning on sequence and structure features
Published in mAbs, 2023
Ameya Harmalkar, Roshan Rao, Yuxuan Richard Xie, Jonas Honer, Wibke Deisting, Jonas Anlahr, Anja Hoenig, Julia Czwikla, Eva Sienz-Widmann, Doris Rau, Austin J. Rice, Timothy P. Riley, Danqing Li, Hannah B. Catterall, Christine E. Tinberg, Jeffrey J. Gray, Kathy Y. Wei
A common building block for the construction of multispecific biologics is the single-chain variable fragment (scFv), consisting of the target-engaging variable heavy chain (VH) linked to the variable light chain (VL) via a flexible linker. Multispecific format platforms such as the BiTE,3 IgG-scFv,4 and XmAb5 incorporate scFv modules. Although scFvs are prevalent in multispecific biologic candidates, they may display sub-optimal physical properties relative to conventional mAbs and generally require sequence modifications to produce a developable asset. One property that is used to gauge the potential developability of a scFv module or scFv-containing multispecific is thermostability – scFv candidates are experimentally screened and/or optimized for thermostability to identify suitable modules.6,7 However, these experiments are resource intensive and time-consuming. Accurate computational methods to predict scFv thermostability from primary amino acid sequence for scFv candidate selection/deselection (and to predict mutations to guide thermostability engineering efforts) would be invaluable to multispecific drug development.
The immunologic aspects of cytokine release syndrome and graft versus host disease following CAR T cell therapy
Published in International Reviews of Immunology, 2022
Vahid Mansouri, Niloufar Yazdanpanah, Nima Rezaei
Immunotherapy serves as an emerging tool for cancer treatment in last three decades [1]. Chimeric antigen receptor (CAR) T cells are the pioneers of this field, which to this date has five FDA-approved products named Kymriah™, Yescarta™ and Tecartus™, Ide-cell™, and Liso-cell™ [2]. CAR T cells are engineered T cells bearing a receptor, designed for detecting tumor-(associated)-antigens. These receptors resemble the variable part of the antibodies, which is called the single-chain variable fragment (scFv) giving a great specific affinity to antigen. These cells benefit from both the cytotoxic ability of T cells and specificity of antibodies, making them a promising tool against cancers [3]. T cells of the donor were converted into the CAR T cells using viral or non-viral vectors to transfer the genetic material responsible for expression of chimeric receptor [4, 5]. Based on the source of the T cells, CAR T cells could be autologous, which is originated from person’s own cells or allogeneic, which is originated from different donor cells [6, 7]. Autologous cells, being from patients themselves, have fewer safety concerns, however, the engineered nature of these cells gives them important additional immunological potencies.
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
Chimeric antigen receptor (CAR)-T cells allow the immuno-oncologist to leverage tumor-directed cytotoxic T-cell function independent of the need for TCR-pMHC interactions. Target specificity is conferred by a concatenation of the heavy and light variable domains of a tumor antigen-specific antibody into a single molecular framework called a single-chain variable fragment (scFv). While this does require the target to be a cell-surface antigen, the antigen can be targeted in its native form. The intracellular portion of the CAR molecule encodes the signaling domains associated with the TCR complex, namely CD3ζ and co-stimulatory molecules, including, but not limited to, CD28 and 4–1BB [66,67]. The result upon antigen recognition of this synthetic receptor is target cell apoptosis mediated by T-cell cytotoxic effector molecules. The anti-tumor efficacy of CD19-directed CAR-T cells for relapsing or refractory hematological malignancies warranted their approval by the FDA in 2017. This treatment paradigm might offer an immunotherapeutic strategy for the greater than 85% of colorectal cancer patients for whom checkpoint blockade is currently not an option, as well as the many MSIHi patients for whom checkpoint inhibition fails.