310 | Nature | Vol 578 | 13 February 2020
Article
60 mg kg−1 (47× the efficacious exposure) did not cause loss of goblet
cells or other gross intestinal defects (Fig. 4c and Extended Data Fig. 8a).
Similarly, 2.5 mg kg−1 ABBV-075 caused germ cell degeneration in the
testes, whereas no microscopic changes in the testes were observed
with 25 mg kg−1 ABBV-744. These efficacy and tolerability results col-
lectively suggest that selectively targeting BD2 can induce antitumour
activity in some cancer settings while mitigating key tolerability issues
of DbBi. These findings support the advancement of ABBV-744 for clini-
cal evaluation (ClinicalTrials.gov identifier NCT03360006) and call
for further investigation of BD2-dependent transcription programs
to reveal additional therapeutic opportunities.
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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.© The Author(s), under exclusive licence to Springer Nature Limited 202002004006008001,0001,2001,400–7 07142128354249Tumour volume (mm3 )Tumour volume (mm3 )Vehicle
ABBV-744
4.7 mg kg–1
ABBV-744
75 mg kg–1ABBV-075
1 mg kg–1Enzalutamide
20 mg kg–1acTreatment period Treatment periodTime (days after initiation of treatment)Time (days after initiation of treatment)02004006008001,0001,200–7 07142128VehicleABBV-744
4.7 mg kg–1
Enzalutamide
20 mg kg–1
ABBV-075
1 mg kg–1bVehicle ABBV-075 ABBV-744Fig. 4 | ABBV-744 maintains DbBi-like activity in AR positive prostate cancer
xenografts while displaying an improved tolerability profile. a, b, Mice
bearing LNCaP (a) or MDA-PCa-2b tumours (b) were treated daily with
enzalutamide, ABBV-075 or ABBV-744 at the indicated amounts using oral
gavage throughout the indicated treatment period. Data are mean ± s.e.m.
(n = 9 mice per group in a) and 7 mice per group in b). Mice treated with
4.7 mg kg−1 ABBV-744 or 1 mg kg−1 ABBV-075 were euthanized on day 28 to
conduct ancillary studies. c, Sprague-Dawley rats (n = 3 animals per group)
were treated daily with vehicle, 3 mg kg−1 ABBV-075 or 60 mg kg−1 ABBV-744 for
14 days. Histopathology assessment was carried out using large-intestinal
sections after necropsy. Alcian blue staining was used to characterize goblet
cells. Representative images of haematoxylin and eosin staining (top) and
alcian blue staining (bottom) are shown. Efficacious exposure levels of
ABBV-075 (1 mg kg−1) and ABBV-744 (4.7 mg kg−1) in mice and exposure levels
associated with the indicated doses of each compound in rats were determined
in separate animals used for pharmacokinetic studies (n = 3 animals).