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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other types of bispecific antibody formats have been designed to overcome certain problems, such as short half-life, immunogenicity, and side effects caused by cytokine liberation. They include chemically linked Fabs [e.g., F(ab’)2]consisting of only the Fab regions (Figure 7.51B), and various types of bivalent and trivalent single-chain variable fragments (scFvs) with fusion proteins mimicking the variable domains of two different antibodies. The most developed of these newer formats are the bispecific T-cell engagers (BiTEs) and mAb2’s, antibody fragments engineered to contain an Fcab antigen-binding fragment instead of the Fc constant region (Figure 7.51C). These different bsMAb formats are explored below in more detail.
Growth Requirements, Binding and Migration of Human Natural Killer Cells
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
Tuomo Timonen, Juha Jääskeläinen, Anna Mäenpää, Tuula Helander, Anatoly Malygin, Panu Kovanen
It is yet uncertain to what extent NK cells actually infiltrate tumor tissue in vivo. NK cells have been recovered from tumor- and renal allograft-infiltrating lymphocyte populations, but the possibility of blood contamination cannot be entirely ruled out. Our in vitro data indicate that CD56+ cells preferentially infiltrate three-dimensional tumor tissue, suggesting that tumor-infiltrating lymphocytes really include NK cells. β2-integrins are pivotal for the infiltration, but it is improbable that they employ the infiltrative capacity of lymphocytes maximally. Nitta and co-workers recently showed that the use of bispecific mAb against CD3 and NCAM strongly improved the results of local adoptive immunotherapy of glioma patients (22). A suitable bispecific antibody, in addition to enchancing the cytotoxicity, may also increase the infiltrative capacity of injected LAK cells. Our spheroid model helps in choosing the proper reagents for maximal destruction of three-dimensional tumor tissue by activated NK cells.
Bispecific Antibodies
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
David M. Segal, Barbara A. Vance, Giuseppe Sconocchia
The simplest way of preparing a bispecific antibody is to chemically crosslink two antibodies using reagents that randomly link the antibodies by amino acid side chain groups, usually ε-amino groups on lysine residues (Segal, 1993; Carlson et al., 1978; Karpovsky et al., 1984; Segal and Bast, 1995) (Figure 2A). The most commonly used reagents for preparing such bsAbs use dithiol exchange reactions, which greatly favor the formation of hetero- over homoconjugates. Randomly crosslinked heteroconjugates work well for most in vitro applications, where, for example, a receptor on a cytotoxic cell needs to be linked to a cell surface component on a target cell. However, because of their heterogeneity in size and chemical composition, and because of variability between batches, heteroconjugates would not give consistent results in vivo, where size and composition greatly effect biodistribution and stability. Instead, homogeneous bispecific molecules are greatly preferred for in vivo animal and clinical studies. Two types of homogeneous bsAbs, the hybrid-hybridoma and the hinge-linked hetero-F(ab’)2 are currently in use, but a number of genetically engineered constructs have recently been described that hold great promise for simplifying the preparation of bispecific molecules. The different types of bsAbs are reviewed in this section.
Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis
Published in Ocular Immunology and Inflammation, 2021
Jerry Chien-Chieh Huang, Matthew Schleisman, Dongseok Choi, Claire Mitchell, Lindsey Watson, Mark Asquith, James T. Rosenbaum
Second, we noted increased IL-17A production by CD8 cells from subjects with AAU. An increase in IL-17A and IL-17F synthesis was noted among MAIT-like cells with AAU. IL-17 has been strongly implicated in spondyloarthritis24, in rodent models of uveitis25,26, and in patients with uveitis.27 However, clinical trials to block IL-17 as a treatment for uveitis have yielded inconsistent results.27,28 An abstract presentation has suggested that blocking IL-17 in patients with spondyloarthritis might reduce the frequency of recurrent AAU (Deodhar, A, presented at EULAR (European League Against Rheumatism), Amsterdam, June, 2018). We believe that this is the first study to implicate IL-17F in the pathogenesis of uveitis. We noted an increase in IL-17F frequency among stimulated MAIT-like cells. IL-17 has several isoforms including predominantly IL-17A and IL-17F. Most clinical trials to date have targeted just IL-17A. A bispecific antibody, bimekizumab, that targets both IL-17A and IL-17F, has shown promising results in a number of clinical trials including one for the treatment of ankylosing spondylitis.29 Our observations support the rationale to use a bispecific antibody.
Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors
Published in mAbs, 2021
Adam R. Root, Gurkan Guntas, Madan Katragadda, James R. Apgar, Jatin Narula, Chew Shun Chang, Sara Hanscom, Matthew McKenna, Jason Wade, Caryl Meade, Weijun Ma, Yongjing Guo, Yan Liu, Weili Duan, Claire Hendershot, Amy C. King, Yan Zhang, Eric Sousa, Amy Tam, Susan Benard, Han Yang, Kerry Kelleher, Fang Jin, Nicole Piche-Nicholas, Sinead E. Keating, Fernando Narciandi, Rosemary Lawrence-Henderson, Maya Arai, Wayne R. Stochaj, Kristine Svenson, Lidia Mosyak, Khetemcnee Lam, Christopher Francis, Kimberly Marquette, Liliana Wroblewska, H. Lily Zhu, Alfredo Darmanin Sheehan, Edward R. LaVallie, Aaron M. D’Antona, Alison Betts, Lindsay King, Edward Rosfjord, Orla Cunningham, Laura Lin, Puja Sapra, Lioudmila Tchistiakova, Divya Mathur, Laird Bloom
The value of the high-throughput protein production system employed in this work was underscored by the need to optimize multiple properties and the observation that optimizing one property can come at the expense of another. For example, removal of predicted T cell epitopes in the anti-CD3 domain led to loss of affinity, and phage selection yielding thermostable GUCY2C domains did not produce hits that altered the H54/H55 asparagine deamidation site despite use of a library designed to do so. The production and testing of over 1600 variants at the 1 mg scale compensated for the relative rarity of designs that achieved a balance among the set of targeted biophysical and functional properties. The availability of protein in formats attuned to specific assays (for example, the rapid thermal stability assay in the scFv-Fc format and affinity measurements in monovalent Fc format) ensured that sequence variants contributing to antibody stability, posttranslational modification, and potential immunogenicity could be evaluated thoroughly. The availability in parallel of proteins in the final therapeutic format – over 500 BsAb were produced for the program – enabled rapid identification of molecules that successfully combined the outputs of multiple strands of optimization. The final result was a well-behaved bispecific antibody suitable for manufacturing and clinical development.
New insights into ErbB3 function and therapeutic targeting in cancer
Published in Expert Review of Anticancer Therapy, 2020
Umbreen Hafeez, Adam C Parslow, Hui K Gan, Andrew M Scott
MM-111 a bispecific fusion protein consisting of two human single chain variable fragments (scFv) antibodies linked by modified human serum albumin and targeted against ErbB2 and ErbB3. It inhibits NRG activated ErbB3 signaling in ErbB2 amplified tumors by preventing the formation of ErbB2/ErbB3 heterodimers (Figure 4). In a randomized phase II trial (NCT01774581) in patients with ErbB2 expressing advanced gastroesophageal cancers, the addition of MM-111 to paclitaxel and trastuzumab resulted in significantly worse OS and PFS. Median PFS in experimental arm (paclitaxel + trastuzumab + MM111) was 9.6 weeks vs 23.3 weeks in control arm (paclitaxel + trastuzumab). Median OS was 32.1 weeks in MM111 arm vs. 56.1 weeks in the control arm. The Data Monitoring Committee closed this trial early. Toxicities reported with this bispecific antibody in combination arms were gastrointestinal side effects, anemia, renal impairment, chest pain, and stomatitis [100]. Given this disappointing result, all further studies of MM-111 were ceased, and the company has ceased further development of MM-111.