Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5625_Библиотеки_им_академика_М_И_Перельмана

To understand carbohydrate-based mAbs in better detail, we will go over some of the basics of the variuos types of antibodies that are produced. There are five differ­ent antibodies that our body generates, namely IgM, IgG, IgD, IgA, and IgE. In the following sections, we will discuss the characteristics of IgG and subclasses along with IgM, scFv, and Fab fragments.

stable, causing a shorter half-life, and needing more frequent dosing with larger doses[25].

A vast amount of new therapeutics that have hit the market are coming from trans­genic animals that can produce fully human antibodies. There are three main

categories of transgenic animals: (i) fully human Ig transloci, (ii) chimeric human Ig transloci, and (iii) Ig knock-out strains. Fully human transloci contain only human V, D, J, and C genes [36]. This technique for fully human Ig loci took off with the implementation of bacterial artificial chromosomes (BACs) and yeast arti­ficial chromosomes (YACs). This allows for much larger (~1 Mb) human IgH and IgL regions to be inserted into an animal genome[37]. Even with this improvement to YAC, it remains difficult to obtain efficient hybridoma production. Due to this challenge, cross-breeding with mice that had a knock-out mutation was invented. The antibodies produced did not perform as well as expected and had little-to-no isotype switching occur, producing mainly IgM antibodies[38]. To overcome these issues, chimeric constructs were suggested as a solution. They are comprised of human V, D, and J linked to a rodent C

in an attempt to overcome the pitfalls of previously developed mAbs. PS A1 is a zwit­terionic polysaccharide (ZPS) capable of triggering a T-cell immune response in the absence of peptides, proteins, or other nonsugar-based material. When compared to commercially available anti-Tn IgM monoclonal Tn-218, using a glycan array, KT-IgM-8 showed a dramatic difference in being able to bind to monovalent Tn at varying concentrations, while commercially available Tn-218 showed virtually no binding to monovalent Tn invitro and induced protection through complement­mediated cytotoxicity in invivo tumor mouse models[43]. MCF-7, a human breast cancer cell line, was xenographed into SCID mice, and KT-IgM-8 showed 40% tumor reduction compared to the control[43].

efficacy against lymphoblastic leukemia[20]. When the Mab216was progressed to phase 2, the scale-up and production proved to be challenging and prevented fur­ther development. The only FDA-approved IgM antibody was called NeutroSpec

therapeutic strategies are highly needed. Frequent relapses are often caused by the loss of heterozygosity of 1p and 11p chromosomes and partial deletions of other chromosomes, which can lead to a loss of critical genes, leaving patients more sus­ceptible to further gene mutations, cancer, and other diseases. Other major prob­lems can be due to amplification of tumor cell growth because of mutations in the MYCN oncogene, which controls the growth, proliferation, and apoptosis of cell, and metastasis of cancerous cells in the liver, bone, and bone marrow [67]. Treatments using dinutuximab or naxitamab are necessary because the complex and aggressive nature of neuroblastoma tumor cells allows them to avoid regular immune responses by evading T cells through down-regulation or losing human leukocyte antigen (HLA) expression. This is a challenge because it interferes with the afferent arm, with the T cells’ ability to find neuroblastoma tumor cells, and with the cytotoxic T lymphocyte (CTL) effector phase of adaptive immunity. Cellular immunity is further impaired by soluble inhibitors such as FAS ligand (FASL) and gangliosides, pro-tumor macrophages, myeloid suppressor cells, and regulatory T cells[68]. Neuroblastoma patients tend to be young with underdeveloped or com­promised immune systems because of the burden of living with an aggressive, high­risk disease and receiving intensive chemotherapy, radiation, or other rigorous treatment that can strain the patient [69]. Because neuroblastoma is so poorly immunogenic for T cells, the patient’s natural immune responses and common can­cer treatments, such as chemotherapy, surgery, or radiation, are not as effective in high-risk neuroblastoma patients[66]. Before immunotherapy options like Unituxin were available, about 40% of high-risk neuroblastoma patients were able to achieve long-term remission, and the 5-year event-free survival (EFS) rates were less than 50%[62, 65, 70]. Because complete eradication of neuroblastoma is rarely possible, dinutuximab is used as a second-line treatment to target any surviving cancer cells and prevent relapse, especially in patients with an advanced version of the disease. In therapeutic trials, patients who received Unituxin had significantly higher EFS rates and overall survival (OS) rates when compared to standard therapy options without Unituxin. EFS rates increased from about 46% to 66%, and OS rates increased from about 75% to 86%[62, 66, 71]. Therefore, including Unituxin treatment cycles as part of the postconsolidation therapy for a patient with high-risk neuroblastoma would help improve patient survival[70].

ch14.18was administered[70, 71]. Immune-stimulating agents known as GM-CSF and interleukin 2 (IL-2) were administered with the mAb to increase the drug’s effectiveness at killing tumor cells. The NCI’s National Clinical Trails Network was a major contributor to these trials [70]. Also, the NCI’s Biopharmaceutical Development Program (BDP) produced the ch14.18 for clinical trials and worked on its process development in order to make the drug available for eligible children suf­fering from high-risk neuroblastoma. In 2010, NCI partnered with a branch of the United Therapeutics Corporation (UTC) to manufacture dinutuximab and gain regulatory approval from the FDA. UTC conducted safety, efficacy, and optimal use studies and gained licensure to manufacture and market dinutuximab under the brand name Unituxin. In 2015, the FDA and European Commission approved Unituxin as a treatment option for pediatric cancer[1, 71, 76].