In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-053-LB-053
Abstract:
Cryptophycins are a class of macrocyclic depsipeptides produced as secondary metabolites by cyanobacteria of the genus Nostoc and were found to bind to microtubules at the vinca site. The natural product C-1 isolated in 1990 and the synthetic derivative C-52 displayed potent in vitro and in vivo antitumor activity in preclinical models. Cryptophycin C-52 (LY355703) produced marginal antitumor activity at MTD in two phase II lung cancer trials and was therefore discontinued. Considering its higher potency versus other tubulin binders such as maytansine and auristatin, this chemical series was selected for an ADC approach. Several conjugates were evaluated in vitro and in vivo based on the conjugation of C52 derivatized at the para-benzylic position of the macrocycle. As described in this study, this optimization led to the discovery of cryptophycin ADC which displayed potent antitumor activity in vivo. However, these conjugates were found unstable in mice plasma while being stable in the plasma of non-rodent species. This species-dependent instability was shown to be the result of a mice plasmatic metabolization of C52 macrocycle once conjugated to the antibody. We therefore designed and synthesized new cryptophycin ADC which exhibited improved plasmatic stability when tested in mice and enhanced therapeutic index in comparison with C52 ADC. In conclusion, these data demonstrated the potent in vitro and in vivo antitumor activity of these new cryptophycin ADC and warrant further development of this cytotoxic payload for an ADC approach. Citation Format: Marie-Priscille Brun, Hervé Bouchard, François Clerc, Jidong Zhang, Pierre-Yves Abecassis, Céline Amara, Eric Beys, Florence Efremenko, Céline Nicolazzi, Marie-Hélène Pascual, Olivier Pasquier, Alain Krick, Pierre-François Berne, Laurence Gauzy, Nathalie Karst, Sylvain Huille, Christophe Henry, Anne-Marie Lefebvre, Ingrid Sassoon. Towards new cryptophycins as promising payloads for ADC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-053.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-LB-053
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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