11 research outputs found
CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin’s lymphoma
ABSTRACTCluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a “don’t eat me” signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20− normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions
ETV6/RUNX1-positive childhood acute lymphoblastic leukemia in China: excellent prognosis with improved BFM protocol
ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy
The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen
Triple
negative breast cancer (TNBC) remains a serious unmet medical
need with discouragingly high relapse rates. We report here the synthesis
and structure–activity relationship (SAR) of a novel series
of 2,4,5-trisubstituted-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidines with potent activity against TNBC tumor cell lines.
These compounds were discovered from a TNBC phenotypic screen and
possess a unique dual inhibition profile targeting TTK (mitotic exit)
and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC
tumor cell assay, identified potent and selective compounds with favorable
in vitro and in vivo activity profiles and good iv PK properties.
This cell-based driven SAR produced compounds with strong single agent
in vivo efficacy in multiple TNBC xenograft models without significant
body weight loss. These data supported the nomination of CC-671 into
IND-enabling studies as a single agent TNBC therapy
CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL
Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223
We report here the synthesis and
structure–activity relationship
(SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase
inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-<i>b</i>]pyrazine-2(1<i>H</i>)-ones were optimized for
in vivo efficacy. These efforts resulted in the identification of
compounds with excellent mTOR kinase inhibitory potency, with exquisite
kinase selectivity over the related lipid kinase PI3K. The improved
PK properties of this series allowed for exploration of in vivo efficacy
and ultimately the selection of CC-223 for clinical development
Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115
We report here the
synthesis and structure–activity relationship
(SAR) of a novel series of triazole containing mammalian target of
rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency,
selectivity, and PK parameters for a series of triazole containing
4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-<i>b</i>]pyrazine-2(1H)-ones resulted in the identification of triazole containing
mTOR kinase inhibitors with improved PK properties. Potent compounds
from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473)
signaling in PC-3 cancer cells, in vitro and in vivo. When assessed
in efficacy models, analogs exhibited dose-dependent efficacy in tumor
xenograft models. This work resulted in the selection of CC-115 for
clinical development
Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223
We report here the synthesis and
structure–activity relationship
(SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase
inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-<i>b</i>]pyrazine-2(1<i>H</i>)-ones were optimized for
in vivo efficacy. These efforts resulted in the identification of
compounds with excellent mTOR kinase inhibitory potency, with exquisite
kinase selectivity over the related lipid kinase PI3K. The improved
PK properties of this series allowed for exploration of in vivo efficacy
and ultimately the selection of CC-223 for clinical development