PMC:4939752 / 11989-14992 JSONTXT

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generation mAbs designed as humanized or fully human with unmodified Fc domain, the purpose of reducing immunogenicity compared to chimeric mAb rituximab. Second generation mAbs include Ocrelizumab, veltuzumab and ofatumumab. Ocrelizumab and veltuzumab are humanized while ofatumumab is fully human antibody. Ocrelizumab (PRO70769, 2H7) is a humanized type I anti-CD20 IgG1 mAb. It has differences in several amino acid positions within the CDRs variable regions of the light and heavy chain as compared to rituximab. Thus it demonstrated superior binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16). Moreover it showed higher ADCC and lower CDC activity as compared to rituximab toward lymphoid malignancies. Currently, this mAb has been evaluated through a phase I/II study in patients with relapsed/ refractory follicular lymphoma (FL) after rituximab failed therapy and showed superior efficacy and safety [32,33]. Veltuzumab is another humanized type I anti-CD20 IgG1 mAb identical to rituximab with single amino acid substitution (Asp101 instead of Asn101) within the CDR3 of the variable heavy chain resulting showed reduced off-rate [13,34]. It also showed anti-proliferative, apoptotic and ADCC effects in vitro similar to rituximab but this modification results more potent binding avidities and a stronger effects on CDC as compared to rituximab [32,35]. In addition, the administration of very low doses either intravenous or subcutaneous routes it showed a potent anti B-cell lymphoma activity in cynomolgus monkeys (Macaca fascicularis) and reduced tumor growth in mice bearing human B-cell lymphomas [34]. Moreover, it achieves efficient delivery into the blood and pharmacologically active when administration subcutaneously compared to other routes. Of these novel mAbs, ofatumumab is at the most advance stage of clinical development with slow off-rate and high CDC activity. Ofatumumab (OFA) is a fully human type I anti-CD20 IgG1κ mAb. It recognizes an overlapping epitope on the small and big extracellular loop of CD20. Moreover, it showed better complement activation as compared to rituximab against both rituximab sensitive and resistant non-Hodgkin lymphomas cell lines expressing high levels of complement defense proteins and low levels of CD20 antigen which failed to undergo CDC with rituximab [36–42]. In addition, it showed higher potential activity than rituximab because of the high capacity for C1q activation. It also showed better response against relapsed/ refractory FL and successively in a phase I/II dose escalation study with an overall response rate (ORR) of 43% [43]. Importantly, in a phase I/II studies on lymphoma and leukemia (specially on CLL) also showed increased complement activity without further increase in toxicity [40,43]. Possibly, the ofatumumab may be give rises to superior efficacy in combination with chemotherapy for tumor clearance and this is being investigated in ongoing trials in both FL and DLBCL."}