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新一代ADC藥代(PK)分析助力產(chǎn)品-抗DXD抗體火熱上市!

日期:2023-11-16 16:13:52

藥代動(dòng)力學(xué)(PK)測定是藥物學(xué)中的一個(gè)重要概念。通過進(jìn)行PK測定,研究人員可以獲得藥物在體內(nèi)吸收、分布、代謝和排泄等數(shù)據(jù)。因此,藥代動(dòng)力學(xué)研究是了解藥物在循環(huán)中的行為以及代謝后形成的最終形式的重要途徑。作為近年來風(fēng)頭正勁的抗體偶聯(lián)藥物(ADC),藥代動(dòng)力學(xué)研究結(jié)果是其臨床試驗(yàn)設(shè)計(jì)的重要參考!今年ADC毫無疑問延續(xù)了其「勢(shì)如破竹」的態(tài)勢(shì),新一代DXD ADC藥物全新升級(jí),成為新型抗腫瘤藥物的突破!


 

DXD-新一代ADC最具前景的有效荷載

甲磺酸鹽Exatecan(DXD)是一種針對(duì)DNA拓?fù)洚悩?gòu)酶I的抑制劑,屬于喜樹堿(CPT)類化合物。DNA拓?fù)洚悩?gòu)酶?抑制劑是目前最具前景的ADC有效荷載,通過裂解單鏈DNA、抑制拓?fù)洚悩?gòu)酶修復(fù)機(jī)制,使得DNA損傷,細(xì)胞凋亡。新一代DXD-ADC藥物使用DXD作為藥物載體(payload),它在血液中的半衰期短,有助于減少毒副作用的產(chǎn)生,且具有強(qiáng)大的細(xì)胞膜滲透能力,產(chǎn)生旁觀者效應(yīng),可殺滅臨近的腫瘤細(xì)胞,半衰期縮短。基于全新的DXd ADC技術(shù),目前已有多款新藥臨床在研:DXd ADC(TDxd/DS-8201/Enhertu)、Dato-DXd(DS-1062)、HER3-DXd(U3-1402/Patritumab deruxtecan)、DS-7300、DS-6000以及DS-3939,分別靶向HER2、Trop2、HER3、B7-H3、CDH6以及MUC1。

DXD-新一代ADC最具前景的有效荷載

圖1. DXD-新一代ADC最具前景的有效荷載 [1]


 

ADC-藥代動(dòng)力學(xué)(PK)

ADC的藥代動(dòng)力學(xué)特征與普通的抗體藥物有相似之處,但同時(shí)也受到其結(jié)合的藥物特性的影響。由于ADC中結(jié)合了小分子藥物,這可能導(dǎo)致ADC的異質(zhì)性增加。在評(píng)估ADC的藥代動(dòng)力學(xué)特征時(shí),研究人員常常使用多種不同的分析物,包括結(jié)合型抗體、總抗體、結(jié)合型效應(yīng)分子、游離小分子毒素及其類似物。

● ADC藥物對(duì)抗體在體內(nèi)的濃度的影響

藥物與抗體的結(jié)合可能會(huì)影響抗體在體內(nèi)的分布、代謝和清除速率,進(jìn)而影響藥物的作用效果和安全性。研究發(fā)現(xiàn),與小分子毒素結(jié)合后抗體的清除速率會(huì)增加,且ADC藥物中的DAR(Drug Antibody Ratio,藥物與抗體的比例)值越高,ADC藥物清除的速率就越快。這說明藥物偶聯(lián)會(huì)加速抗體的清除過程,而高比例的藥物結(jié)合可能會(huì)進(jìn)一步加速這一過程,這種作用機(jī)制是ADC藥物在腫瘤治療中的關(guān)鍵特征之一。

● ADC藥物濃度降低的清除途徑:

1. 抗體部分通過酶降解等方式解體:ADC藥物中的抗體部分可能會(huì)在體內(nèi)經(jīng)過代謝途徑被酶降解,導(dǎo)致ADC藥物整體濃度減少。

2. 分子毒素從抗體上完全解離(即DAR(Drug Antibody Ratio)變?yōu)?):這意味著毒性分子與抗體分離,失去了與抗體結(jié)合的能力。

ADC藥物降解途徑

圖2. ADC藥物降解途徑 [2]

● ADC藥物在體內(nèi)的損失率的評(píng)估

藥物損失率是指ADC(抗體藥物偶聯(lián)物)中藥物有效成分(payload)的損失率。在ADC中,藥物有效成分通常是通過與抗體共價(jià)結(jié)合來實(shí)現(xiàn)靶向遞送。藥物損失可能會(huì)降低藥物的靶向性和療效,甚至產(chǎn)生不良反應(yīng)。因此,對(duì)ADC藥物在體內(nèi)的損失率進(jìn)行評(píng)估是研發(fā)和評(píng)估臨床前ADC藥物安全性和療效的重要一環(huán)。

結(jié)合抗體PK與總抗PK的差異性大,說明ADC中藥物在體內(nèi)的丟失或降解速率的變化大??贵w的濃度變化速率與ADC藥物的清除速率的差異間接反映了ADC藥物在血液中的穩(wěn)定性,因?yàn)樗绊懥怂幬镌隗w內(nèi)的停留時(shí)間和效果。

ADC藥物的清除速率往往比總抗?jié)舛雀?。藥物分解和ADC自身的清除兩個(gè)過程一起導(dǎo)致了ADC中藥物濃度下降,而總抗?jié)舛葍H受ADC和未與藥物結(jié)合的抗體的清除速度影響。如果總抗體的消失速度較快而ADC藥物的清除速率較低,這可能意味著藥物在體內(nèi)的釋放速率較慢??赡艿臋C(jī)制包括藥物與抗體結(jié)合過于牢固,或者藥物分子釋放機(jī)制存在障礙。

ELISA測定總抗和偶聯(lián)抗體

圖3. ELISA測定總抗和偶聯(lián)抗體 [3]

為鼎力協(xié)助科研和藥企人員針對(duì)DXD-ADC的藥代動(dòng)力學(xué)分析,華美CUSABIO推出PK研究工具DXD Monoclonal Antibody,具有高特異性、高穩(wěn)定性、高靈敏度,能夠有效測定DXD的穩(wěn)定性和釋放效率,可用于ADC藥物的血漿/血清動(dòng)力學(xué)分析、藥物結(jié)合親和力的測定、DAR值分析以及ADC藥物的療效評(píng)估等。這將加快DXD-ADC藥物研發(fā)過程,通過評(píng)估DXD-ADC的藥代動(dòng)力學(xué)特性,為其臨床前應(yīng)用和劑量優(yōu)化提供依據(jù)。

華美CUSABIO: DXD Monoclonal Antibody

DXD Monoclonal Antibody Code: CSB-MA996977I2m

DXD antibody on SDS-PAGE under reducing (R) condition
DXD antibody on SDS-PAGE under reducing (R) condition

The purity of the protein is greater than 90%.

The Binding Activity of ADC-DXD(1) with Anti-DXD antibody
The Binding Activity of ADC-DXD(1) with Anti-DXD antibody

Activity: Measured by its binding ability in a functional ELISA. Immobilized ADC-DXD(1) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 2.298 to 3.054 ng/mL.

The Binding Activity of ADC-DXD(2) with Anti-DXD antibody
The Binding Activity of ADC-DXD(2) with Anti-DXD antibody.

Activity: Measured by its binding ability in a functional ELISA. Immobilized ADC-DXD(2) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 2.566 to 3.233 ng/mL.

The Binding Activity of T-DXd(DS-8201) with Anti-DXD antibody
The Binding Activity of T-DXd(DS-8201) with Anti-DXD antibody.

Activity: Measured by its binding ability in a functional ELISA. Immobilized T-DXd(DS-8201) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 2.529 to 3.340 ng/mL.

DXD Monoclonal Antibody Code: CSB-MA996977I1m

DXD antibody on SDS-PAGE under reducing (R) condition.
DXD antibody on SDS-PAGE under reducing (R) condition

The purity of the protein is greater than 90%.

The Binding Activity of ADC-DXD(1) with Anti-DXD antibody
The Binding Activity of ADC-DXD(1) with Anti-DXD antibody

Activity: Measured by its binding ability in a functional ELISA. Immobilized ADC-DXD(1) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 1.840 to 2.253 ng/mL.

The Binding Activity of ADC-DXD(2) with Anti-DXD antibody
The Binding Activity of ADC-DXD(2) with Anti-DXD antibody.

Activity: Measured by its binding ability in a functional ELISA. Immobilized ADC-DXD(2) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 2.365 to 2.835 ng/mL.

The Binding Activity of T-DXd(DS-8201) with Anti-DXD antibody
The Binding Activity of T-DXd(DS-8201) with Anti-DXD antibody.

Activity: Measured by its binding ability in a functional ELISA. Immobilized T-DXd(DS-8201) at 2 μg/mL can bind Anti-DXD antibody, the EC50 is 2.225 to 2.851 ng/mL.


參考文獻(xiàn):

[1] https://xueqiu.com/8965749698/192610616

[2] Kamath, Amrita V., and Suhasini Iyer. "Preclinical pharmacokinetic considerations for the development of antibody drug conjugates." Pharmaceutical research 32 (2015): 3470-3479.

[3] Lin K, Tibbitts J, Shen B Q. Pharmacokinetics and ADME characterizations of antibody–drug conjugates[J]. Antibody-Drug Conjugates, 2013: 117-131.