There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction ca...There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.展开更多
Little had been known about ETO protein until t(8;21) was found in 12%―15% of acute myeloid leukemia which resulted in AML1-ETO fusion protein. ETO protein has four conserved nervy homology regions termed NHR1― 4. A...Little had been known about ETO protein until t(8;21) was found in 12%―15% of acute myeloid leukemia which resulted in AML1-ETO fusion protein. ETO protein has four conserved nervy homology regions termed NHR1― 4. A lot have already been known about NHR1, 2, 4: NHR1 is homologous with the Drosophila TATA-box-associated factor 110 (TAF110); NHR2 is a dimerization domain associated with mSin3A/HDAC; NHR4 is MYND class of zinc fingers associated with NCoR/SMRT/HDAC. Only the function of NHR3 remains unclear. In order to investigate whether NHR3 domain could participate in oligomerization, we cloned and purified this domain. Through gel filtration chromatography, dynamic light scattering and dissolved crystal electrophoresis, we found that NHR3 domain was a tight tetramer. Then we cloned NHR3+4 domain (i.e. NHR3 domain plus NHR4 domain), and discovered, by gel filtration chromatography and native PAGE, that NHR3+4 domain could form dimer in solution. This was the first time to ob- serve that NHR3 and NHR4 domains may have some con- tribution to the oligomerization of ETO protein, which might recruit corepressors in the form of dimer, and stabilize ETO dimerization through convergent strength of NHR2, NHR3 and NHR4 domains and then stabilize corepressors recruit- ment. These speculations are very worthy of further evalua- tion.展开更多
文摘There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.
基金This work was supported by the National Natural Science Foundation of China(Grant No.30370300).
文摘Little had been known about ETO protein until t(8;21) was found in 12%―15% of acute myeloid leukemia which resulted in AML1-ETO fusion protein. ETO protein has four conserved nervy homology regions termed NHR1― 4. A lot have already been known about NHR1, 2, 4: NHR1 is homologous with the Drosophila TATA-box-associated factor 110 (TAF110); NHR2 is a dimerization domain associated with mSin3A/HDAC; NHR4 is MYND class of zinc fingers associated with NCoR/SMRT/HDAC. Only the function of NHR3 remains unclear. In order to investigate whether NHR3 domain could participate in oligomerization, we cloned and purified this domain. Through gel filtration chromatography, dynamic light scattering and dissolved crystal electrophoresis, we found that NHR3 domain was a tight tetramer. Then we cloned NHR3+4 domain (i.e. NHR3 domain plus NHR4 domain), and discovered, by gel filtration chromatography and native PAGE, that NHR3+4 domain could form dimer in solution. This was the first time to ob- serve that NHR3 and NHR4 domains may have some con- tribution to the oligomerization of ETO protein, which might recruit corepressors in the form of dimer, and stabilize ETO dimerization through convergent strength of NHR2, NHR3 and NHR4 domains and then stabilize corepressors recruit- ment. These speculations are very worthy of further evalua- tion.
