Targeted tumour therapy has proved to be an efficient alternative to overcome the
limitations of conventional chemotherapy. The upregulation of the bombesin receptor
2 (BB2) in several malignancies and the advantages offered by peptide drug conjugates
over antibody drug conjugates in terms of production and tumour targeting motivated
us to synthesise and test bombesin conjugates armed with the tubulin binder monomethyl
auristatin E. The widely used Val-Cit-PABC was initially included as cathepsin cleavable
self-immolative linker for the release of the free drug. However, the poor stability
of the Val-Cit-conjugates in mouse plasma encouraged us to consider the optimised
alternatives Glu-Val-Cit-PABC and Glu-Gly-Cit-PABC. Conjugate BN-EVcM1, featuring
Glu-Val-Cit-PABC, combined suitable stability (t(½) in mouse and human plasma: 8.4
h and 4.6 h, respectively), antiproliferative activity in vitro (IC50 = 29.6 nM on
the human prostate cancer cell line PC-3) and the full release of the free payload
within 24 h. Three conjugates, namely BN-EGcM1, BN-EVcM1 and BN-EVcM2, improved the
accumulation of MMAE in PC-3 human prostate cancer xenograft mice models, compared
to the administration of the free drug. Among them, BN-EVcM1 also stood out for the
significantly extended survival of mice in in vivo acute efficacy studies and for
the significant inhibition of the growth of a PC-3 tumour in mice in both acute and
chronic efficacy studies.
