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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Known as “Immunoliposomes”, another immunoconjugate approach involves the attachment of antibodies to the surface of nanoparticles such as liposomes which can be filled with cytotoxic or radioactive agents (also useful for imaging), or even nucleic acids suitable for gene therapy. Once the mAb has guided the nanoparticle to the tumor site, the agent within is then released where it can exert a therapeutic effect.
Tumor Spheroids in Studies of Immunotherapy
Published in Rolf Bjerkvig, Spheroid Culture in Cancer Research, 2017
Studies on multicellular spheroids have shown heterogeneity in the binding of monoclonal antibodies, and the heterogeneity was dependent both on the types of cells and on the types of antibodies or antibody fragments applied.31–35 Cell and antibody-dependent variations in the therapeutic effects after exposure to 131I-labeled immunoconjugates have also been demonstrated.40–42 The variations in therapeutic effects were mainly dependent on the amount of binding, but it is reasonable to assume that there also was an influence of the heterogeneity. This has to be studied in more detail. It is necessary to analyze therapeutic effects from specific antibodies labeled not only with 131I, but also with other radioactive nuclides (e.g., 90Y, 199Au,211At, 212Bi), stable nuclides for neutron capture therapy (e.g., 10B, 157Gd), and with other toxic agents, such as toxins to allow optimization of antibody-mediated immunotherapy.
Marrow Purging And Stem Cell Preparation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Denis C. Roy, Nadine Beauger, Martin Gyger
In an attempt to facilitate the use of mAbs by rendering them directly cytotoxic, several groups have developed immunoconjugates. Thus, M195, an anti-CD33 mAb, conjugated with iodine 131 was able to target marrow cells and demonstrated significant leukemic cytoreduction after in vivo administration (Schwartz et al., 1993). However, with a range of β-emission of approximately 50 cell diameters, ex vivo purging with such radioactive conjugates would most likely cause irreversible damage to bystander-stem cells, preventing their in vitro use. Immunotoxins (ITs) represent another alternative, and Myers et al. were the first to produce an IT directed against AML cells by conjugating AML-2-23 (anti-CD14) and MCS-2 (anti-CD13) mAbs to the ribosome-inactivating phytotoxin, ricin (Myers et al., 1988). Ricin consists of two subunits, the A and B chains, which are linked by a single disulfide bond as well as noncovalent interactions (Vitetta et al., 1987; Blakey and Thorpe, 1988). The A chain is an enzyme which inactivates the 60S subunit of eukaryotic ribosomes, and the B chain binds to galactose-terminated oligosaccharides that are ubiquitous on eukaryotic cell surfaces. Thus, lactose was added in vitro to block non-specific binding of the whole ricin fraction of the ITs to normal cells (Myers et al., 1988). Both ITs selectively bound to target cells, inhibited protein synthesis, and prevented the clonogenic growth of fresh marrow blasts from AML patients as well as KG-1 (AML) cells. Tecce et al. rather used saporin emitoxin (SAP) conjugates, which demonstrated low cytotoxicity in unconjugated form, and highly specific cytotoxicity and favorable pharmacokinetic properties once conjugated to LAM3 and LAM7 mAbs (Tecce et al., 1991). These ITs yet suffered from a narrow spectrum of activity against monocytes and M5b AML. Nevertheless, the fact that immunotoxins do not necessitate the complicated standardization procedures associated with complement use, nor the sophisticated apparatus required for magnetic purging methods, warrants further developments in this field (Arbour et al., 1996).
What are the challenges involved in the strategies for future antibody-drug conjugate discovery and development for oncology?
Published in Expert Opinion on Drug Discovery, 2023
Sajeli Ahil Begum, Ahmed Kamal
Antibody-drug conjugates (ADCs) or immunoconjugates are powerful biopharmaceutical agents widely developed for oncology and hematology, as well as for the delivery of other classes of drugs, such as antibiotics, anti-inflammatory, etc. These therapeutics combine monoclonal antibodies (mAbs) with very potent drugs connected via a chemical linker to deliver highly targeted activity. ADCs for treating tumors are well developed, with 12 conjugates approved by US-FDA by the end of 2021 (Mylotrag®, Adcetris®, Kadcyla®, Besponsa®, Lumoxiciti®, Polivy®, Enhertu®, Padcev®, Trodelvy®, Blenrep®, Zynlonta®, and Tivdak®) [1]. The structures of two newly approved ADCs are presented in Figure 1. The mechanism of targeted actions of anticancer ADCs is mainly through (i) selective binding of the antibody to the surface antigens present on a particular tumor cell, (ii) internalization in the cancer cell, and (iii) lysosomal degradation, and release of the cytotoxic payload, leading to cytotoxic cell death [1,2].
Reduction of therapeutic antibody self-association using yeast-display selections and machine learning
Published in mAbs, 2022
Emily K. Makowski, Hongwei Chen, Matthew Lambert, Eric M. Bennett, Nicole S. Eschmann, Yulei Zhang, Jennifer M. Zupancic, Alec A. Desai, Matthew D. Smith, Wenjia Lou, Amendra Fernando, Timothy Tully, Christopher J. Gallo, Laura Lin, Peter M. Tessier
We expect many creative applications of the methods reported here in the future. First, the ease of preparing immunoconjugates with different fluorescent properties and types of immobilized molecules creates opportunities for multiplexing and preparing diverse types of conjugates using unique types of antibodies (e.g., polyclonal antibodies), proteins (e.g., albumin) and complex biological mixtures (e.g., serum, cell lysates). Second, while it was not the goal of this study to increase affinity or introduce species cross-reactivity, it would be straightforward to implement our workflow during antibody engineering campaigns aimed at such goals. Both antibody engineering objectives commonly lead to selection of mutations that increase the risk of poor biophysical properties, including increased antibody self-association and reduced stability. The availability of robust screening reagents for de-selecting antibody mutations that compromise key biophysical properties while selecting mutations that enhance specific binding properties is expected to accelerate the predictable generation of antibodies with drug-like properties.
Monoclonal antibodies used for the management of hemataological disorders
Published in Expert Review of Hematology, 2022
Kanjaksha Ghosh, Kinjalka Ghosh
Some of the side effects of antibody therapeutics are common and relate to hypersensitivity reaction to a protein and complement activation. This side effect is universal and is taken care of by slow infusion, paracetamol and prior corticosteroid and anti-allergic medications. These reactions are immediate. Some reactions, particularly in malignant hematological disorders, depend on malignant cell load. Higher the load, more severe is the reaction. Tumor lysis syndrome as seen with chemotherapy may also be seen with MoAbs. Cytokine release syndrome (CRS) due to killing or immune activation of cells are also seen with several antibodies. Antibodies which suppress immune function can precipitate various types of infections especially CMV, herpes virus activation, or progressive multifocal leukoencephalopathy. Immune check point inhibitors in addition produce other side effects specific to endocrine system due to autoimmune endocrinopathies. Hence, for each monoclonal antibody, there could be specific side effects and hypersensitivity reaction. These drugs should be handled carefully and not only detailed knowledge and experience for its use is required but also understanding of so many biosimilars and new antibodies that are hitting the market every year are required. The package insert of each product should also be carefully read before using them. The safety and side effects of MoAbs have been reviewed elsewhere [24,32,107]. Antibody immunoconjugates produce additional and peculiar side effects [8,9]. Some of the antibodies have ophthalmic, cardiac, hepatic, and hematological side effects.