抗體—藥物共軛連結(jié)技術(shù)(ADC)是一種將基因工程單株抗體與殺癌細(xì)胞藥物結(jié)合在一起的技術(shù),。在7月出版的《自然—生物技術(shù)》期刊上，研究人員報(bào)告一種具有癌癥治療潛力的新型ADC技術(shù),，這種方法有望減少藥物對(duì)健康細(xì)胞的傷害，副作用也更小,。
在敏銳識(shí)別癌細(xì)胞的同時(shí),，以腫瘤為靶標(biāo)的抗體也能忽略正常細(xì)胞，抗體的這種特征被用于靶向藥物輸送的研發(fā)中,，研究人員希望將化學(xué)治療藥物縛束到這種抗體上,，形成ADC藥物。以前制造ADC藥物的方法具有多種混合效果,，部分抗體會(huì)比其他抗體攜帶更多的藥物，因此很難確定最佳的藥物用量,。
如今,，美國(guó)Genentech公司W(wǎng)illiam Mallet和同事研制出一種可確定攜帶藥物量的ADC藥物制造新方法。與以前的方法相比,，化學(xué)治療藥物以一種可繁殖的方式被縛束在抗體上,，因此對(duì)健康細(xì)胞的副作用就更少。他們?cè)诳贵w的結(jié)構(gòu)上修改了特別位點(diǎn)以促進(jìn)藥物的縛束,，同時(shí)又不會(huì)影響抗體的整體結(jié)構(gòu)或識(shí)別癌細(xì)胞的能力,。
對(duì)模式小鼠的研究顯示，這種新型ADC藥物比傳統(tǒng)的ADC藥物更有效：只有一半劑量的藥物就能殺死同樣多的癌細(xì)胞,。而且,，對(duì)兔子和猴子來(lái)說(shuō)，它們對(duì)這種新型的ADC藥物具有更好的耐受性,，意味著這種藥物對(duì)人有更小的副作用,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature Biotechnology，doi:10.1038/nbt.1480,，Jagath R Junutula,，William Mallet
Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index
Jagath R Junutula1, Helga Raab1, Suzanna Clark1, Sunil Bhakta1, Douglas D Leipold1, Sylvia Weir1, Yvonne Chen1, Michelle Simpson1, Siao Ping Tsai1, Mark S Dennis1, Yanmei Lu1, Y Gloria Meng1, Carl Ng1, Jihong Yang1, Chien C Lee1, Eileen Duenas1, Jeffrey Gorrell1, Viswanatham Katta1, Amy Kim1, Kevin McDorman1,2, Kelly Flagella1, Rayna Venook1, Sarajane Ross1, Susan D Spencer1, Wai Lee Wong1, Henry B Lowman1, Richard Vandlen1, Mark X Sliwkowski1, Richard H Scheller1, Paul Polakis1 & William Mallet1
AbstractAntibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display–based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.
1 Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
2 present address: Division of Pathology, Charles River Preclinical Services, Nevada, 6995 Longley Lane, Reno, Nevada 89511, USA.
