Third generation anti-CD20 mAbs include AME133v, Pro131921 (v114), GA101, R603/EMAB-6 and TRU-015. They are ongoing in early phases of clinical development. AME-133v (LY2469298, ocaratuzumab) is an Fc protein engineered humanized type I IgG1 mAb which currently being evaluated in a Phase I/II dose escalation study in patients with relapsed/refractory follicular B-cell NHL [44]. In vitro study suggested that it has 13 to 20 fold more binding affinity with CD20 and 5–7 fold higher avidity to the low affinity (F/F and F/V) variants of FcγRIIIa receptor thereby improving killing of B-cell NHL ~10 fold as compared to rituximab [44–46]. Although, the clinical trial with AME-133v are currently ongoing and it will need to be compared to rituximab in randomized clinical trials to substantiate its potential clinical advantages. Pro131921 (v114) is derived from 2H7. It is another humanized IgG1 Fc protein engineered antibody and displays 30-fold more binding affinity to the low variant of FcγR (RIIIa: FF or FV) over rituximab [47–49]. In vitro study revealed that it has higher binding affinity showed improved ADCC activity about 10 fold more as compared to rituximab. Although, preclinical studies in non-human primates (cynomolgus monkeys; Macaca fascicularis) revealed that treatment with Pro13192 is associated in a dose-dependent reversible neutropenia and thrombocytopenia [49]. However, Phase I/II clinical studies demonstrated better anti-tumor efficacy in patients with relapsed and /or refractory indolent lymphoma who failed rituximab containing regimens [50]. But, clinical development has been recently terminated due to assess safety of escalating doses of Pro13192 in patients with NHL and CLL. LFB-R603/EMAB-6 (Ublituximab, LFP) is another chimeric glyco-engineered IgG1 mAb showed enhanced FcγRIII affinity. It was raised in rat cell lines YB2/0 using EMABLING technology thus resulting in naturally low fucose contents in its Fc region [51]. LFB-R603/EMAB-6 has similar CDC and PCD activities whereas ADCC response rate found about 35% higher at 50ng/ml while rituximab induced less than 5% at the same concentration in low CD20 expressing CLL cells [51]. Furthermore, preclinical studies also revealed that it can disrupt NF-κB/Snail/RKIP/PTEN/AKT signaling in B-cell NHL cell lines that are resistant to chemotherapy and immuno-chemotherapy [52]. It is currently in a Phase I/II clinical study in CLL. In contrast to the other anti-CD20 mAbs GA101 (RO5072759, obinutuzumab) also known as the gazyva is the first fully humanized type II IgG1 mAb which have glycol-engineered Fc domain with non-fucosylated oligosaccharides to enhance the interaction with FcγRs particularly FcγRIIIa (CD16) therefore showed enhancing ADCC activity compared to other anti-CD20 mAbs [53–56]. Recently (in November 2013) it has FDA approved mAb for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL). Preclinical studies suggested that the modified Fc region of GA101 improved about 50 fold binding affinity to FcγRIII and 10 to 100 fold increased cell death through ADCC mechanism against CD20 positive NHL cell lines [57–60]. Moreover, in vitro study also demonstrated that modification in elbow hinge regions promotes direct programmed cell death mechanism in several NHL cell lines and primary malignant B-cells [12,49]. However, these modifications result in reduced CDC activity [61]. GA101 has also showed superior therapeutic efficacy in subcutaneous lymphoma xenograft models of diffuse large B-cell lymphoma and mantle cell lymphoma when used as monotherapy or in combination with cyclophosphamide [62–65]. As compared to rituximab GA101 showed significantly superior B-cell depletion not only in peripheral blood but also in spleen and lymph nodes in non-human primates and hCD20 transgenic mice [61,63,64,66–68]. GA101 demonstrated a favorable safety profile with no dose-limiting toxicities during phase I/II study in patients with relapsed/refractory CD20 positive cells including CLL, DLBCL and other NHLs [69]. Moreover, the pharmacokinetics of GA101 is mostly comparable to those of rituximab and dose-dependent. However, the significant inter and intra-patient variabilities have been observed. Therefore, the clinical relevance further will need to be investigation. TRU-015 ((CytoxB20G) is a single chain anti- CD20 molecule that is a small modular immuno-pharmaceutical drug composed of human IgG1 Fc and CH2 and CH3 hinge regions which linked directly to an anti-CD20 specific Fv regions [70–72]. It has high ADCC and low CDC activating potential. It is currently in Phase II clinical development for inflammatory disease is ongoing particularly against rheumatoid arthritis [73,74].