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Development of Novel ADCs: Conjugation of Tubulysin Analogues to Trastuzumab Monitored by Dual Radiolabeling

Author(s): R. Cohen, D. J. Vugts, G. W. Visser, M. Stigter-van Walsum, M. Bolijn, M. Spiga, P. Lazzari, S. Shankar, M. Sani, M. Zanda, G. A. van Dongen

Abstract:
Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that are interesting for application in antibody-drug conjugates (ADC). For full control over drug-antibody ratio (DAR) and the effect thereof on pharmacokinetics and tumor targeting, a dual-labeling approach was developed, wherein the drug, tubulysin variants, and the antibody, the anti-HER2 monoclonal antibody (mAb) trastuzumab, are radiolabeled. (131)I-radioiodination of two synthetic tubulysin A analogues, the less potent TUB-OH (IC50 > 100 nmol/L) and the potent TUB-OMOM (IC50, approximately 1 nmol/L), and their direct covalent conjugation to (89)Zr-trastuzumab were established. Radioiodination of tubulysins was 92% to 98% efficient and conversion to N-hydroxysuccinimide (NHS) esters more than 99%; esters were isolated in an overall yield of 68% +/- 5% with radiochemical purity of more than 99.5%. Conjugation of (131)I-tubulysin-NHS esters to (89)Zr-trastuzumab was 45% to 55% efficient, resulting in ADCs with 96% to 98% radiochemical purity after size-exclusion chromatography. ADCs were evaluated for their tumor-targeting potential and antitumor effects in nude mice with tumors that were sensitive or resistant to trastuzumab, using ado-trastuzumab emtansine as a reference. ADCs appeared stable in vivo. An average DAR of 2 and 4 conferred pharmacokinetics and tumor-targeting behavior similar to parental trastuzumab. Efficacy studies using single-dose TUB-OMOM-trastuzumab (DAR 4) showed dose-dependent antitumor effects, including complete tumor eradications in trastuzumab-sensitive tumors in vivo. TUB-OMOM-trastuzumab (60 mg/kg) displayed efficacy similar to ado-trastuzumab emtansine (15 mg/kg) yet more effective than trastuzumab. Our findings illustrate the potential of synthetic tubulysins in ADCs for cancer treatment. Cancer Res; 74(20); 5700-10. (c)2014 AACR.

Full version: Available here

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ISBN: 1538-7445 (Electronic) 0008-5472 (Linking)
Publication Year: 2014
Periodical: Cancer Res
Periodical Number: 20
Volume: 74
Pages: 5700-10
Author Address: Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands. Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands. KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Pula, Cagliari, Italy. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel. KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Pula, Cagliari, Italy. Dipartimento C.M.I.C. del Politecnico di Milano and C.N.R.-I.C.R.M., Milano, Italy. Dipartimento C.M.I.C. del Politecnico di Milano and C.N.R.-I.C.R.M., Milano, Italy. Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom. Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands. Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands. gams.vandongen@vumc.nl.