Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants.
Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants.
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DOI：
10.1084/jem.20131660
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发表时间：
2014-02-10
期刊：
影响因子：
--
通讯作者：
Watts RJ
中科院分区：
文献类型：
--
作者：
Bien-Ly N;Yu YJ;Bumbaca D;Elstrott J;Boswell CA;Zhang Y;Luk W;Lu Y;Dennis MS;Weimer RM;Chung I;Watts RJ
高亲和力转铁蛋白受体（TfR）双特异性抗体促进TfR转运到溶酶体，诱导TfR降解，从而降低TfR介导血脑屏障转细胞作用的能力。转铁蛋白受体抗体（TfR）具有进入大脑治疗的潜在用途。我们已经证明，抗TfR和β-分泌酶（BACE1 [β-淀粉样蛋白切割酶-1]）的双特异性抗体可穿过血脑屏障（BBB），有效降低脑内β淀粉样蛋白水平。我们发现优化抗tfr亲和力可以改善脑暴露和BACE1抑制。在这里，我们探讨了这种改善的细胞基础，并探讨了TfR抗体亲和力是否改变了TfR的细胞内运输。比较体内高亲和力和低亲和力的TfR双特异性抗体，我们发现与TfR的高亲和力结合导致脑TfR水平的剂量依赖性降低。体外活体成像和共定位实验显示，高亲和力的TfR双特异性抗体促进了TfR向溶酶体的转运，从而诱导了TfR的降解，这一观察结果在体内得到了进一步的证实。重要的是，高亲和力抗TfR剂量诱导脑TfR水平降低，这显著降低了脑暴露于第二剂量低亲和力抗TfR双特异性。因此，高亲和力抗TfR可改变TfR转运，从而显著影响TfR介导血脑屏障转胞酌的能力。
High-affinity transferrin receptor (TfR) bispecific antibodies facilitate trafficking of TfR to lysosomes and induce TfR degradation to decrease the ability of TfR to mediate BBB transcytosis. Antibodies to transferrin receptor (TfR) have potential use for therapeutic entry into the brain. We have shown that bispecific antibodies against TfR and β-secretase (BACE1 [β-amyloid cleaving enzyme-1]) traverse the blood–brain barrier (BBB) and effectively reduce brain amyloid β levels. We found that optimizing anti-TfR affinity improves brain exposure and BACE1 inhibition. Here we probe the cellular basis of this improvement and explore whether TfR antibody affinity alters the intracellular trafficking of TfR. Comparing high- and low-affinity TfR bispecific antibodies in vivo, we found that high-affinity binding to TfR caused a dose-dependent reduction of brain TfR levels. In vitro live imaging and colocalization experiments revealed that high-affinity TfR bispecific antibodies facilitated the trafficking of TfR to lysosomes and thus induced the degradation of TfR, an observation which was further confirmed in vivo. Importantly, high-affinity anti-TfR dosing induced reductions in brain TfR levels, which significantly decreased brain exposure to a second dose of low-affinity anti-TfR bispecific. Thus, high-affinity anti-TfR alters TfR trafficking, which dramatically impacts the capacity for TfR to mediate BBB transcytosis.
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影响因子：
14.8
作者：
Holtmaat, Anthony;Bonhoeffer, Tobias;Chow, David K.;Chuckowree, Jyoti;De Paola, Vincenzo;Hofer, Sonja B.;Huebener, Mark;Keck, Tara;Knott, Graham;Lee, Wei-Chung A.;Mostany, Ricardo;Mrsic-Flogel, Tom D.;Nedivi, Elly;Portera-Cailliau, Carlos;Svoboda, Karel;Trachtenberg, Joshua T.;Wilbrecht, Linda
通讯作者：
Wilbrecht, Linda
影响因子：
4.6
作者：
Manich, Gemma;Cabezon, Itsaso;Vilaplana, Jordi
通讯作者：
Vilaplana, Jordi
DOI：
10.1523/jneurosci.0033-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bien-Ly N;Gillespie AK;Walker D;Yoon SY;Huang Y
通讯作者：
Huang Y
影响因子：
4.2
作者：
FISHMAN, JB;RUBIN, JB;FINE, RE
通讯作者：
FINE, RE
影响因子：
64.8
作者：
JEFFERIES, WA;BRANDON, MR;MASON, DY
通讯作者：
MASON, DY