1.Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy.
Yusuke MIMURA ; Toshihiko KATOH ; Radka SALDOVA ; Roisin O'FLAHERTY ; Tomonori IZUMI ; Yuka MIMURA-KIMURA ; Toshiaki UTSUNOMIYA ; Yoichi MIZUKAMI ; Kenji YAMAMOTO ; Tsuneo MATSUMOTO ; Pauline M RUDD
Protein & Cell 2018;9(1):47-62
Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next-generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
Animals
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Antibodies, Monoclonal
;
adverse effects
;
pharmacokinetics
;
therapeutic use
;
Glycosylation
;
Humans
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Immunoglobulin G
;
chemistry
;
metabolism
;
Protein Engineering
;
methods
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Receptors, Fc
;
chemistry
;
metabolism
;
Treatment Outcome
2.Switching between eltrombopag and recombinant human thrombopoietin in patients with immune thrombocytopenia: an observational study.
Xuan CAI ; Haixia FU ; Xiangyu ZHAO ; Jin LU ; Qian JIANG ; Yingjun CHANG ; Xiaojun HUANG ; Xiaohui ZHANG
Chinese Medical Journal 2022;135(19):2344-2350
BACKGROUND:
Recombinant human thrombopoietin (rh-TPO) and eltrombopag are two distinct TPO receptor agonists (TPO-RAs) with different mechanisms. During the pandemic, when immunosuppressive medications are controversial, switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA. We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia (ITP) patients.
METHODS:
This prospective, open-label, observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People's Hospital in China. The study evaluated response rates and platelet counts at different time points after the switch, bleeding events, time to response, duration of response, and adverse events.
RESULTS:
At 6 weeks after switching, response was observed in 21/49 patients (43%) who switched for inefficacy and 34/47 patients (72%) who switched for non-efficacy-related issues. In the inefficacy group, 9/27 patients (33%) responded to eltrombopag, and 12/22 patients (55%) responded to rh-TPO. In the non-efficacy-related group, 21/26 (81%) and 13/21 (62%) patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching, respectively. Response at 6 months was achieved in 24/49 patients (49%) switching for inefficacy and 37/47 patients (79%) switching for non-efficacy issues. In the inefficacy group, 13/27 patients (48%) responded to eltrombopag, and 11/22 patients (50%) responded to rh-TPO. In the non-efficacy-related group, 22/26 patients (85%) and 15/21 patients (71%) in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching, respectively. Both eltrombopag and rh-TPO were well tolerated.
CONCLUSIONS:
Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA. When the switch was motivated by other reasons, including patient preference and platelet count fluctuations, the probability of response was high.
REGISTRATION
ClinicalTrials.gov, NCT04214951.
Adult
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Humans
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Purpura, Thrombocytopenic, Idiopathic
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Thrombopoietin/adverse effects*
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Prospective Studies
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Recombinant Fusion Proteins
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Receptors, Fc/therapeutic use*
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Receptors, Thrombopoietin/therapeutic use*
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Thrombocytopenia/chemically induced*
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Benzoates/adverse effects*
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Hydrazines/adverse effects*
3.A novel therapeutic anti-HBV antibody with increased binding to human FcRn improves in vivo PK in mice and monkeys.
Ciming KANG ; Lin XIA ; Yuanzhi CHEN ; Tianying ZHANG ; Yiwen WANG ; Bing ZHOU ; Min YOU ; Quan YUAN ; Chi-Meng TZENG ; Zhiqiang AN ; Wenxin LUO ; Ningshao XIA
Protein & Cell 2018;9(1):130-134