64 research outputs found
AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL
Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50<30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed
Dual Neonate Vaccine Platform against HIV-1 and M. tuberculosis
Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the
world's most devastating diseases. The first vaccine the majority of
infants born in Africa receive is Mycobacterium bovis bacillus
Calmette-Guérin (BCG) as a prevention against TB. BCG protects against
disseminated disease in the first 10 years of life, but provides a variable
protection against pulmonary TB and enhancing boost delivered by recombinant
modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of
M. tuberculosis is currently in phase IIb evaluation in
African neonates. If the newborn's mother is positive for human
immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring
HIV-1 through breastfeeding. We suggested that a vaccination consisting of
recombinant BCG expressing HIV-1 immunogen administered at birth followed by a
boost with rMVA sharing the same immunogen could serve as a strategy for
prevention of mother-to-child transmission of HIV-1 and rMVA expressing an
African HIV-1-derived immunogen HIVA is currently in phase I trials in African
neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1
and TB consisting of BCG.HIVA administered at birth followed by a boost with
MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed,
in which the transgene transcription is driven by either modified H5 or short
synthetic promoters, respectively, and tested for immunogenicity alone and in
combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless
and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher
levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c
mice. A BCG.HIVA222–mMVA.HIVA.85A prime-boost regimen induced
robust T cell responses to both HIV-1 and M. tuberculosis.
Therefore, proof-of-principle for a dual anti-HIV-1/M.
tuberculosis infant vaccine platform is established. Induction of
immune responses against these pathogens soon after birth is highly desirable
and may provide a basis for lifetime protection maintained by boosts later in
life
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