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  • These agents can be divided into three categories based upon

    2022-05-17

    These agents can be divided into three categories based upon the therapeutic agent conjugated to the antibody; the most frequently explored are ADCs using a cytotoxic agent to be delivered directly to the tumor site. The second Sitagliptin phosphate monohydrate class has not been broadly used and consists of radionucleotides (Wong et al., 2004). The third class includes catalytic toxins which have been explored widely with promising results across both hematologic diseases and solid tumors (Kreitman et al., 2005, Hassan et al., 2013). To date, three ADCs have been approved by the Food and Drug Administration (FDA): gemtuzumab ozogamicin for the treatment of relapsed CD-33 positive acute myeloid leukemia in older patient population, brentuximab vedotin for the treatment of relapsed or refractory Hodgkin's lymphoma and relapsed systemic anaplastic large-cell lymphoma, and T-DM1 for treatment of metastatic HER2-positive breast cancer (Sievers et al., 2001, Younes et al., 2010, Verma et al., 2012). The successful application of T-DM1 in metastatic HER2-positive breast cancer patient populations has further encouraged the development of ADCs for the treatment of other solid tumors (Verma et al., 2012, Petersdorf et al., 2013). Although gemtuzumab ozogamicin was recently withdrawn from the market when further studies showed no benefit, the significant clinical benefit of by T-DM1 and brentuximab vedotin provides compelling evidence that clinical development of novel immunoconjugates could be greatly beneficial. Currently, several ADCs are being studied including among others, inotuzumab ozogamicin in leukemia and lymphoma, glembatumumab vedotin in breast cancer and melanoma, lorvotuzumab mertansine in CD56 expressing hematological malignancies (NCT02420873).
    Guanylyl cyclase C (GCC) GCC is a Sitagliptin phosphate monohydrate membrane receptor of guanylin (Currie et al., 2006), uroguanylin (Hamra et al., 1999), lymphoguanylin (Forte et al., 1999), and heat-stable enterotoxin (STa), a peptide of enteric Escherichia coli. GCC is expressed by the epithelial cells of the GI tract from the small bowel to the rectum. In the esophagus and stomach, GCC expression was identified only in the intestinal metaplasia of the gastroesophageal junction even without high-grade dysplasia as well as gastric carcinoma. (Schulz et al., 1993). In enterocytes of the intestinal villi, intracellular cGMP elevation caused by STa binding to GCC mediates cGMP elevation and stimulates cGKII, leading to phosphorylation and activation of cystic fibrosis transmembrane conductance regulator (CFTR), which stimulates intestinal fluid secretion and diarrhea (Vaandrager et al., 1998). In animal models a disruption of the guanylyl cyclase-C gene leads to a heat-stable enterotoxin-resistant phenotype (Mann et al., 1997, Schulz et al., 1997). GCC is a member of the guanylyl cyclase (GC) family of proteins which includes at least seven forms, A through G. Endogenous ligands, however, have been identified only for forms A, B and C. GCs are involved in regulation of intracellular cGMP concentrations (Tamura et al., 2001). GCC is involved in the G protein signaling cascade that is activated by low intracellular calcium levels and inhibited by high intracellular calcium levels (Sakurai et al., 2011). On the other hand, GCC is a tumor suppressor and it is regulated by caudal type homeobox transcription factor-2 (CDX-2) and it prevents cancer cells proliferation (Pitari et al., 1997).
    Future perspectives Low chemotherapy drug potency, unstable linkers and low antigen selectivity have all been attributed to the low chemotherapeutic drug potency (Perez et al., 2014). The ideal linker should be stable so that the ADC does not release the cytotoxic drug before reaching its target in the surface of tumor cell and causing off-target toxicity. At the same, time the linker should be developed to release the drug efficiently once internalized (Teicher & Chari, 2011). In parallel to other characteristics of ADCs, the quality of linkers has improved and will continue to be an area for improvement.