Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. Methods We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Results Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. Conclusions This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. Clinical trials registration NCT01987362.

Interleukin 1 (IL-1) receptor antagonist (IL-

The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Human interleukin 113 (IL-113) exerts its diverse biological effects by binding to specific receptors on target cells. Two ypes of IL-1 receptor (IL-1R) have been identified: the type I IL-1R (p80) and the type II IL-1R (p68). Using site-specific mutagenesis, we have identified the binding site on IL-11 for the murine type I IL-1R. Analogs of the IL-1fL protein containing defined amino acid substitutions were produced and tested for competitive binding to the two IL-1Rs. Substitutions of the amino acids at seven positions resulted in analogs that had .100-fold reductions in competitive binding to the type I IL-1R, while maintaining substantial binding to the type II IL-1R. These seven amino acids (Arg-4, Leu-6, Phe-46, Ile-56, are clustered in the IL-13 molecule, forming a discontinuous binding site. The side chains of all seven residues are exposed on the surface of IL-14. The cumulative binding energies contributed by each of the residues predict a binding affinity that is consistent with the observed Kd of the wild-type protein for the type I IL-1R.Human interleukins la and 1,B (IL-la and IL-1*3) are polypeptide hormones that share limited identity in amino acid sequence but are functionally similar and exhibit a multiplicity of biological activities. Their diverse biological effects indicate that IL-1 is one of the major mediators in the regulation of immunologic and inflammatory responses (1-3). Both IL-la and IL-1p8 bind to the same receptors on different cell types with high affinity (4-6). Two types of IL-1 receptor (IL-lR) have been identified. The IL-lR that is present on T cells is an 80-kDa glycoprotein that has been molecularly cloned from mouse and human cells (7,8 MATERIALS AND METHODSBacterial Strains and Plasmids. The Escherichia coli expression plasmid for human IL-1f, pEV1-IL-lbeta, has been described (27). Oligonucleotide-directed mutagenesis was performed as described (27). For each mutation, a specific restriction site was included in the synthetic oligonucleotide to monitor the incorporation of the mutated sequence at the correct location in the IL-1p8 coding region. Mutations were confirmed by nucleotide sequence analysis as described (28).Preparation of IL-1(3 Analog Proteins. Crude extracts. Bacterial cells containing the wild-type or mutated IL-1p3 expression plasmids were grown at 300C to early logarithmic phase (OD6w = 0.5) in M9 medium. The cultures were then induced for protein synthesis by transfer to 420C for --2 h, until OD600 = 1.0 ± 0.1. Samples of the cultures were then pelleted by centrifugation at 12,000 x g for 20 min at 40C. Extracts were made from the cell pellets by vigorous Vortex mixing and heating at 1000C in Laemmli sample buffer (29). The extracted proteins were analyzed by SDS/PAGE to assess the size and levels of expression of the IL-1.3 analog proteins, relative to that of wild-type IL-1,3 induced in parallel cultures.Purified proteins. Pellets of E. coli cells induced for 8 synthesis were disrupted by sonication and then adjusted to pH 4 with 6 M HCL....

BACKGROUND Sarilumab (anti-interleukin-6 receptor-alpha; monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODS We performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS Four-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], − 7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD − 5.5%; 95% CI, −20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSION In hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit.