Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability

Article

Author: Kinyamu-Akunda, Jacqueline ; Lähteenmäki, Tuula ; Heiskanen, Annamari ; Saarinen, Juhani ; Helin, Jari ; Aitio, Olli ; Rittase, William ; Pitkänen, Virve ; Dudkin, Vadim ; Geist, Brian ; Kotiranta, Titta ; Irrechukwu, Onyi ; Burke, Krista ; Klein, Donna M. ; Pynnönen, Henna ; Satomaa, Tero ; Zhou, Junguo ; Kohli, Neeraj ; Hiltunen, Jukka O. ; Niemelä, Ritva ; Goldberg, Shalom D. ; Hänninen, Anna-Liisa ; Aina, Olulanu ; Wiley, Kristen

AbstractAntibody–drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab–auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo antitumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). The trastuzumab–MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared with a valine–citrulline conjugated trastuzumab ADC (trastuzumab–vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab–MMAU at drug-to-antibody ratios (DAR) of eight and four respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab–vc-MMAE. Trastuzumab–MMAUDAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. The optimized trastuzumab–MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in nonhuman primates, leading to a superior preclinical therapeutic window. The data support potential utility of trastuzumab–MMAU for treatment of HER2+ tumors.

01 Oct 2016·European Journal of Pharmaceutical SciencesQ2 · MEDICINE

HER2-targeted antibody drug conjugates for ovarian cancer therapy

Q2 · MEDICINE

Article

Author: Huang, Min ; Zhang, Jing ; Li, Shenjun ; Ma, Weiwei ; Zhang, Xiuli ; Dong, Lihou ; Wang, Chunhua ; Fang, Jianmin ; Wang, Ling ; Chen, Fang ; Wang, Lei ; Xu, Qiaoyu ; Jiang, Jing ; Huang, Changjiang

HER2 targeted delivery of ovarian cancer therapy has been beneficial for some patients, although, its efficacy is yet to be confirmed in large populations. We generated a novel anti-HER2 humanized antibody (Hertuzumab) and conjugated it to a microtubule-disrupting drug monomethyl auristatin E conjugate (MMAE) with a lysosomal protease-cleavable valine-citrulline linker. The average drug to antibody ratio (DAR) of Hertuzumab-vc-MMAE was varied by conjugating Hertuzumab antibodies with increasing linker-drugs (LDs) from D0-D8. The resulting conjugates were tested for kinetic affinity for soluble HER2-ECD, cytotoxicity, and in vivo pharmacokinetics. The kinetic binding constant values (KD) were obtained by the bio-layer interference (BLI) method. The half time (t1/2) and clearance (Cl) results of the pharmacokinetic profile in rats were DAR-dependent. Hertuzumab-vc-MMAE with DAR4 was selected for further evaluation. Both Hertuzumab and Hertuzumab conjugates could bind to HER2 antigen, and exhibited significant cytotoxicity on HER2 positive tumor cells after internalization by receptor-mediated endocytosis. Hence, Hertuzumab-vc-MMAE conjugates were significantly selective both in vitro and in vivo as compared to other ovarian cancer clinical therapies that are currently used. Cell signal transduction and cell cycle were also affected, as shown by down regulation of PI3K/AKT pathway and arrested mitosis in the G2/M phase. The pharmacokinetics and pharmacodynamics (PK-PD) of the conjugates in nude mouse xenograft model demonstrated a correlation between efficacy and drug concentration. These results show that Hertuzumab-vc-MMAE is a potential therapeutic agent for HER2 positive ovarian cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	University of Copenhagen	-

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