China 
Africa 
Explore chapters and articles related to this topic
Lung Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
ROS1 is another member of the insulin receptor superfamily of RTK with marked sequence homology to ALK. ROS1 is not expressed in the normal lung. Furthermore, the function of wild-type ROS1 is poorly understood, and the ligand is unknown. Several ROS1 fusion partners, the most frequent of which is CD74, have recently been identified in 1% to 2% of patients with NSCLC.38 These lead to constitutive activation of RTKs and subsequent phosphorylation of MAPK, PI3K, and JAK-STAT. ROS1 fusions occur in a similar clinical population as ALK fusions. Crizotinib, a multitargeted TKI that potently targets ROS1, is the only currently approved therapy for treatment of ROS1-rearranged NSCLC. Approval was based on an expansion cohort of the PROFILE 1001 Phase I study, in which crizotinib induced an overall response rate of 72% with a PFS of 19.2 months. Despite impressive responses, most patients will relapse within 2 years, and in the largest cohort of crizotinib-resistant ROS1-rearranged NSCLC cases, most of the tumors harbored ROS1 mutations (i.e., on-target resistance). The most frequently observed resistance mutation was the solvent front G2032R, which is analogous to ALKG1202R. The multitargeted TKI cabozantinib has preclinical activity against the solvent front mutations that have been identified in crizotinib resistance, including G2032R and D2033N. Lorlatinib is also a potent inhibitor of ROS1.
Anti-infectious innate and adaptive immune responses
Published in Gabriel Virella, Medical Immunology, 2019
Carl Atkinson, Gabriel Virella
Macrophage migration inhibitory factor. MIF, one of the first cytokines discovered and one of the last to be characterized, bridges the gap between innate and adaptive immunity. It is expressed by a variety of cells, including monocytes, macrophages, neutrophils, activated T cells, and anterior pituitary cells. Its release by leukocytes is triggered by the exposure to microbial products, such as LPS, Gram-positive exotoxins, or other pro-inflammatory cytokines (TNF, IFNγ). Several receptors of MIF have been identified, including CD74, CXCR2 and CXCR4. MIF appears to be involved in the recruitment of leukocytes in conjunction with other proinflammatory cytokines, whose release is also stimulated by MIF. It also increases the expression of TLR-4, thus playing a significant role in anti-infectious defense against Gram-negative bacteria. However, experimental data suggest that excessively high levels of MIF may actually exacerbate the effects of endotoxin. This may result from immunoregulatory properties of MIF, which can inhibit the immunosuppressive effects of glucocorticoids on immune cells and p53-dependent macrophage apoptosis, both effects leading to enhanced adverse inflammatory responses.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The enhanced understanding of the genetic events and immune microenvironment has facilitated a greater application of targeted and immunological therapies for patients with relapsed and rituximab refractory FL. In such patients, earlier studies with the BTK inhibitor, ibrutinib, resulted in a modest efficacy, possibly due to the presence of coexisting mutations, such as CARD11, which are now considered to confer resistance to ibrutinib. Several novel anti-CD20 monoclonal antibodies, such as veltuzumab, as monotherapy and in combination with the anti-CD74, milatuzumab and ocrartuzumab (AME-133) are ongoing. There appears to be greater promise for epigentically targeted therapies (such as tazemetostat, an EZH2 inhibitor) and vorinostat (a histone deactylase inhibitor). Studies are also testing the inclusion of immune checkpoint inhibitors and CAR T-cell specific for CD19, a differentiation antigen expressed in B-cells and B lineage malignancies. The next generation of novel antibody-based therapies, such as bispecific antibodies, which combine the specificity of two antibodies, so they can bind to different antigens. Bispecific T-cell engager (BiTE) binds CD3 on T-cells and an antigen on tumour cells to activate T-cells to kill the cancer cells. The first-in-class BiTE antibody, blinatumomab, which specifically targets CD19 on B-cells, was approved in 2014 for clinical use in patients with relapsed or refractory ALL and is now being tested in FL, and preliminary results when the drug is administered at very low doses are encouraging.
An updated patent review of Mcl-1 inhibitors (2020–2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Jingjing Liu, Fangkui Yin, Ziqian Wang, Ting Song, Zhichao Zhang
In 2020, Novartis disclosed Mcl−1 inhibitor-based ADCs in two patents (WO2020/236817 and WO2020/236825) [58,59]. In the patent of WO2020/236817, a series of CD74-targeting Mcl−1 ADC were disclosed [58]. CD74 is an established and attractive target for antibody–drug conjugates due to its restricted expression on normal tissues and significant upregulation in a range of hematological malignancies. The ability of Mcl−1 ADCs to inhibit cell proliferation and survival was assessed using a CellTiter-Glo luminescent assay. One exemplary CD74-targeting ADC 13 (Figure 12b) exhibited IC50 of 0.03–1.45 nM in various DLBCL cells. In an acute myeloid leukemia model, the CD74-targeting ADC induced a tumor growth inhibition of 32.7% after intravenous (IV) administration at 30 mg/kg once for 9 days.
Current and emerging pharmacotherapy for the treatment of childhood acute myeloid leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Branko Cuglievan, David McCall, Lindsay Robusto, M. Estela Mireles, Suzanne C. Gettys
CD74 is a chaperone for major histocompatibility class II molecules (HLA-DR–associated invariant chain) involved in antigen presentation [91,92]. CD74 is expressed alone or with HLA-DR in a wide range of hematologic malignancies and solid tumors and has been related with disease progression and metastasis in solid tumors. Its expression has been proposed to serve as a prognostic factor in many neoplasms, with higher expression associated with oncogenesis [93,94]. In addition, expression of CD74 in pediatric AML patients correlates with response to bortezomib [95]. Recently, a novel CD74-targeting antibody drug conjugate, STRO-001, has been tested in B-cell malignancies (non-Hodgkin lymphoma and multiple myeloma) with encouraging results [96]. These data suggest CD74 could be a candidate for CAR-targeted therapies, and expanded trials looking at CD74 targeting should be performed.
Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis
Published in Scandinavian Journal of Rheumatology, 2020
C Vinci, M Infantino, S Raturi, A Tindell, LM Topping, R Strollo, H Amital, Y Shoenfeld, S Gertel, V Grossi, M Manfredi, IM Rutigliano, F Bandinelli, F Li Gobbi, A Damiani, P Pozzilli, IB Mcinnes, CS Goodyear, M Benucci, A Nissim
Total IgA levels have previously been shown to be elevated in patients with axSpA (39, 40). Franssen et al investigated the possible association between serum IgA, IgM, and IgG and disease activity in a 1 year longitudinal study in patients with active SpA receiving regular DMARD treatment with either phenylbutazone or diflunisal. Throughout the study, changes in IgA, but not in IgM and IgG, correlated with changes in disease activity. Similarly to our result, changes in serum IgA and erythrocyte sedimentation rate (ESR) showed no consistent correlation, suggesting that the two parameters reflect different aspects of disease (41). Previous studies detected IgA autoantibodies against cluster of differentiation 74 (CD74) with a high prevalence in patients with established spondoloarthritis (9, 10). CD74 plays a role in preventing premature binding of peptides to major histocompatibility complex class II. In addition, CD74 has an impact on B-cell differentiation. A multicentre study conducted by the same group compared the sensitivity and specificity of anti-CD74 and HLA-B27 in patients with non-radiographic axSpA and found that IgA anti-CD74 may help to improve the diagnostic value of HLA-B27 to diagnose axSpA and the identification of IgA anti-CD74 antibodies without, and particularly with, the simultaneous presence of HLA-B27 (42). This, however, was not supported in a follow-up study that reported a lack of sufficient specificity to yield significant diagnostic value of anti-CD74 IgA (11).