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Recent Advances of Nanotechnologies for Cancer Immunotherapy Treatment
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Immune checkpoints are crucial for maintaining immune homeostasis and preventing autoimmunity as they are regulators of immune system. However, increasing research has identified that in various types of cancer, the intrinsic mechanisms of immune checkpoint are overactivated resulting in escaping immune surveillance on tumor cells. Owning to the overactivation of immune checkpoint, a majority of effector T cells would differentiate into exhausted T cells at late stage of diseases. The inhibitory receptors are normally overexpressed on exhausted T cells, and effector cytokines’ secretion is also decreased [18]. Thus, it is vital to recover T cells’ effector function and reverse immunosuppressive tumor microenvironment to improve potent antitumor immunity. In many preclinical trials, it has been demonstrated that immune checkpoint inhibitors could release inhibitory mechanisms of T-cell-mediated immunity and promote CTL responses [19]. Immune checkpoint inhibitors, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, indoleamine 2,3-dioxygenase (IDO), cluster of differentiation 47 (CD47), cluster of differentiation 40 (CD40), and 4-1BB (CD137), are at the forefront of immunotherapy for a variety of cancers. The expression patterns, intrinsic signaling pathways, and mechanisms of these immune checkpoint inhibitors are quite different from each other despite of some commonalities. The two major kinds of antibodies, CTLA-4 and PD-1/PD-L1 axis, have exhibited significant clinical successes and provided great potential in cancer immunotherapy [20,21].
Expression of a recombinant anti-programed cell death 1 antibody in the mammary gland of transgenic mice
Published in Preparative Biochemistry & Biotechnology, 2021
Guihua Gong, Wei Zhang, Liping Xie, Lei Xu, Shu Han, Youjia Hu
With the rapid growing of the monoclonal antibody market, reports of expression of antibodies in the milk of transgenic animals have been published increasingly. Since monoclonal antibodies contain a heavy chain and a light chain, two constructs containing the genes encoding both chains were used simultaneously for their expression in transgenic animals. The highest expression level of monoclonal antibodies reported in transgenic mice is 32 g/L using the vector pBC1, a plasmid marketed by Invitrogen for recombinant protein production in transgenic animals. Two cassettes encoding the HC and LC of a neutralizing anti-hepatitis A virus antibody were co-microinjected at a ratio of 1:1 into pronucleus of zygotes to generate the transgenic mice.[53] Van et al.[54] reported the expression of a mouse-human chimeric anti-CD19 mAbs in transgenic mice at an approximate level of 0.5 g/L. Transgenic mice were obtained by co-injection of two separate expression cassettes containing bovine β-lactoglobulin promoter and mouse anti-CD19 variable (V) region genes which were combined with human Ig gamma1 heavy and kappa light chain constant region genes.[55] used the commercial pBC1 vector, which consists of aβ-casein promoter from goat and 2 × HS4 insulator, to express anti-CD20 mAbs in the milk of transgenic mice with an expression level of 17 g/L. The strategy of transgenic mice generation is the same as Van et al.[54] except that the variable region was derived from mouse anti-human CD20 antibody. Antibodies expressed in milk of transgenic goat was reported in Pollock et al.[56] with a level of 14 g/L. Based on their platform of transgenic goats, GTC Biotherapeutics has produced a novel chimeric anti-CD20 IgG1 named TG20, which has demonstrated a significantly higher cytotoxic activity of Rituximab. Expression levels of TG20 vary from 2 to 10 g/L among 7 independent transgenic goat lines[57]. In addition to TG20, GTC has also developed a portfolio of monoclonal antibodies for use as follow-on biologics[58]. For example, an aglycosylated anti-137 antibody was expressed in milk of transgenic goats. This antibody can be used as an antagonist of the CD137/CD137L interaction, which was involved in the treatment of inflammatory conditions including atherosclerosis and sepsis[17].