A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL.
© 2016 John Wiley & Sons Ltd.

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Advances in the Development of Site-Specific Antibody-Drug Conjugation.

Antibody-drug conjugates (ADCs) showed strong anticancer efficacy in the clinic. However, the current conventional technologies generate conjugates with undefined attachment sites and heterogeneous profiles containing different sub-populations, leading to potential off-target toxicity. In order to reduce the variability and heterogeneity associated with the ADCs generated using conventional technologies, several site-specific antibody-drug conjugation strategies were developed for the next generation of ADCs. These strategies include cysteine-targeted conjugation by engineering a free cysteine into the antibody or by placing a thiol bridge on cysteines in hinge disulfides. Glutamine-targeted conjugation was also demonstrated by coupling the drug-linker to glutamine residues through an engineered glutamine tag or a native glutamine, as well as an additionally introduced glutamine residue in aglycosylated antibody mutant using microbial transglutaminase. The site-specific conjugation of drug-linker to antibody carbohydrates was developed either through metabolic engineering or a chemo-enzymatic approach. Other amino acids, such as unnatural amino acids or amino acid derivatives introduced through protein engineering, have also been shown to be efficient targets for site-specific conjugation. The sitespecific ADCs with homogeneous profiles and well-defined conjugation sites were obtained using these second generation ADC methods and showed potent in vitro cytotoxicity and strong in vivo antitumor activity. These results suggest that newly developed site-specific conjugation technologies can potentially be applied in producing the next generation ADC for cancer treatment in the clinic with high therapeutic index.

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Sequential and compartmentalized action of Rabs, SNAREs and MAL in the apical delivery of fusiform vesicles in urothelial umbrella cells.

Uroplakins (UPs) are major differentiation products of urothelial umbrella cells, playing important roles in forming the permeability barrier, and in the expansion/stabilization of the apical membrane. Further, UPIa serves as a uropathogenic E. coli receptor. While it is understood that UPs are delivered to the apical membrane via fusiform vesicles (FVs), the mechanisms that regulate this exocytic pathway remain poorly understood. Immuno-microscopy of normal and mutant mouse urothelia showed that the UP-delivering FVs contained Rab8/11 and Rab27b/Slac2-a, which mediate apical transport along actin filaments. Subsequently, a Rab27b/Slp2-a complex mediated FV-membrane anchorage before SNARE-mediated and MAL-facilitated apical fusion. We also showed that keratin 20 (K20), which formed a chicken-wire network 150-300 nm below the apical membrane and had hole sizes allowing FV passage, defined a subapical compartment containing FVs primed and strategically located for fusion. Finally, we showed that Rab8/11 and Rab27b function in the same pathway, that Rab27b-knockout leads to uroplakin and Slp2-a destabilization, and that Rab27b works upstream from MAL. These data support a unifying model in which UP cargoes are targeted for apical insertion via sequential interactions with Rabs and their effectors, SNAREs and MAL, and in which K20 plays a key role in regulating vesicular trafficking.
© 2016 by The American Society for Cell Biology.

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Development of Teratocarcinomas and Teratomas in Severely Immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/Szj (NSG) Mice.

The embryonic portion of 7-day-old mouse embryos transplanted to extrauterine sites of syngeneic adult animals gives rise to teratoid tumors, which may be either benign [teratomas (T)] or malignant [teratocarcinomas (TC)]. The incidence of embryo-derived TC varies from one mouse strain to another, indicating that some strains are TC-permissive whereas others are relatively TC-nonpermissive. Embryos of a TC-permissive mouse strain (DBA/2J) and a TC-nonpermissive one (C57BL/6J) were transplanted into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice to determine their tumorigenic potential in the absence of functional adaptive and innate immune responses in the hosts. C57BL/6J embryos transplanted to NSG mice gave rise to TC in 31% of cases, whereas the incidence of TC produced from DBA/2J transplanted embryos was 71%. The NSG embryos transplanted to syngeneic hosts gave rise to TC in 67% of cases, allowing the classification of NSG as a TC-permissive strain. A previously reported correlation between teratocarcinoma and splenomegaly was also observed in the NSG mice. The capacity of these tumors to differentiate into the cells and tissues of the normal embryo is mapped through a detailed histological analysis. These data suggest that teratocarcinogenesis, in the absence of host innate and adaptive immunity, is largely determined by the genetic background of the embryo.

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Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer.

Defects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-X(L), and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-X(L) for survival.
To identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-X(L) in a panel of cell lines using a selective and potent BCL-X(L) inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-X(L) were further undertaken via a variety of genetic manipulations.
We identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-X(L) via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity.
This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-X(L) in mediating the survival of specific tumor types, and indicate that BCL-X(L) inhibition could be an effective treatment for colorectal tumors with high BCL-X(L) and NOXA expression.

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