TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity.

Cluster of differentiation 38 (CD38) is an ecto-enzyme expressed primarily on immune cells that metabolize nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose or cyclic ADP-ribose and nicotinamide. Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate and nicotinamide mononucleotide, a critical NAD+ precursor in the salvage pathway. NAD+ is an important coenzyme involved in several metabolic pathways and is a required cofactor for the function of sirtuins (SIRTs) and poly (adenosine diphosphate-ribose) polymerases. Declines in NAD+ levels are associated with metabolic and inflammatory diseases, aging, and neurodegenerative disorders. To inhibit CD38 enzyme activity and boost NAD+ levels, we developed TNB-738, an anti-CD38 biparatopic antibody that pairs two non-competing heavy chain-only antibodies in a bispecific format. By simultaneously binding two distinct epitopes on CD38, TNB-738 potently inhibited its enzymatic activity, which in turn boosted intracellular NAD+ levels and SIRT activities. Due to its silenced IgG4 Fc, TNB-738 did not deplete CD38-expressing cells, in contrast to the clinically available anti-CD38 antibodies, daratumumab, and isatuximab. TNB-738 offers numerous advantages compared to other NAD-boosting therapeutics, including small molecules, and supplements, due to its long half-life, specificity, safety profile, and activity. Overall, TNB-738 represents a novel treatment with broad therapeutic potential for metabolic and inflammatory diseases associated with NAD+ deficiencies.Abbreviations: 7-AAD: 7-aminoactinomycin D; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cell-mediated phagocytosis; ADPR: adenosine diphosphate ribose; APC: allophycocyanin; cADPR: cyclic ADP-ribose; cDNA: complementary DNA; BSA: bovine serum albumin; CD38: cluster of differentiation 38; CDC: complement dependent cytotoxicity; CFA: Freund's complete adjuvant; CHO: Chinese hamster ovary; CCP4: collaborative computational project, number 4; COOT: crystallographic object-oriented toolkit; DAPI: 4',6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; DSC: differential scanning calorimetry; 3D: three dimensional; εNAD+: nicotinamide 1,N6-ethenoadenine dinucleotide; ECD: extracellular domain; EGF: epidermal growth factor; FACS: fluorescence activated cell sorting; FcγR: Fc gamma receptors; FITC: fluorescein isothiocyanate; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IgG: immunoglobulin; IFA: incomplete Freund's adjuvant; IFNγ: Interferon gamma; KB: kinetic buffer; kDa: kilodalton; KEGG: kyoto encyclopedia of genes and genomes; LDH: lactate dehydrogenase; M: molar; mM: millimolar; MFI: mean fluorescent intensity; NA: nicotinic acid; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NAM: nicotinamide; NGS: next-generation sequencing; NHS/EDC: N-Hydroxysuccinimide/ ethyl (dimethylamino propyl) carbodiimide; Ni-NTA: nickel-nitrilotriacetic acid; nL: nanoliter; NK: natural killer; NMN: nicotinamide mononucleotide; OD: optical density; PARP: poly (adenosine diphosphate-ribose) polymerase; PBS: phosphate-buffered saline; PBMC: peripheral blood mononuclear cell; PDB: protein data bank; PE: phycoerythrin; PISA: protein interfaces, surfaces, and assemblies: PK: pharmacokinetics; mol: picomolar; RNA: ribonucleic acid; RLU: relative luminescence units; rpm: rotations per minute; RU: resonance unit; SEC: size exclusion chromatography; SEM: standard error of the mean; SIRT: sirtuins; SPR: surface plasmon resonance; µg: microgram; µM: micromolar; µL: microliter.

Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design.

RATIONALE: Colorectal cancer (CRC) is preventable through screening, with colonoscopy and fecal occult blood testing comprising the two most commonly used screening tests. Given the differences in complexity, risk, and cost, it is important to understand these tests' comparative effectiveness. STUDY DESIGN: The CONFIRM Study is a large, pragmatic, multicenter, randomized, parallel group trial to compare screening with colonoscopy vs. the annual fecal immunochemical test (FIT) in 50,000 average risk individuals. CONFIRM examines whether screening colonoscopy will be superior to a FIT-based screening program in the prevention of CRC mortality measured over 10 years. Eligible individuals 50-75 years of age and due for CRC screening are recruited from 46 Veterans Affairs (VA) medical centers. Participants are randomized to either colonoscopy or annual FIT. Results of colonoscopy are managed as per usual care and study participants are assessed for complications. Participants testing FIT positive are referred for colonoscopy. Participants are surveyed annually to determine if they have undergone colonoscopy or been diagnosed with CRC. The primary endpoint is CRC mortality. The secondary endpoints are (1) CRC incidence (2) complications of screening colonoscopy, and (3) the association between colonoscopists' characteristics and neoplasia detection, complications and post-colonoscopy CRC. CONFIRM leverages several key characteristics of the VA's integrated healthcare system, including a shared medical record with national databases, electronic CRC screening reminders, and a robust national research infrastructure with experience in conducting large-scale clinical trials. When completed, CONFIRM will be the largest intervention trial conducted within the VA (ClinicalTrials.gov identifier: NCT01239082).

De-Risking Immunotherapy: Report of a Consensus Workshop of the Cancer Immunotherapy Consortium of the Cancer Research Institute.

With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials.

Racial and ethnic differences in health care utilization and outcomes among ulcerative colitis patients in an integrated health-care organization.

BACKGROUND: Current knowledge of racial disparities in healthcare utilization and disease outcomes for ulcerative colitis (UC) is limited. We sought to investigate these differences among Caucasian, African American, Asian, and Hispanic patients with ulcerative colitis in Kaiser Permanente, a large integrated health-care system in Northern California. METHODS: This retrospective cohort study used computerized clinical data from 5,196 Caucasians, 387 African-Americans, 550 Asians, and 801 Hispanics with prevalent UC identified between 1996 and 2007. Healthcare utilization and outcomes were compared at one and five-year follow-up by use of multivariate logistic regression analysis. RESULTS: Compared with whites, the male-to-female ratio differed for African-Americans (0.68 vs. 0.91, p < 0.01) and Asians (1.3 vs. 0.91, p < 0.01). Asians had fewer co-morbid conditions (p < 0.01) than whites, whereas more African-Americans had hypertension and asthma (p < 0.01). Use of immunomodulators did not differ significantly among race and/or ethnic groups. Among Asians, 5-ASA use was highest (p < 0.05) and the incidence of surgery was lowest (p < 0.01). Prolonged steroid exposure was more common among Hispanics (p < 0.05 at 1-year) who also had more UC-related surgery (p < 0.01 at 5-year) and hospitalization (<0.05 at 5-year), although these differences were not significant in multivariate analysis. CONCLUSIONS: In this population of UC patients with good access to care, overall health-care utilization patterns and clinical outcomes were similar across races and ethnicity. Asians may have milder disease than other races whereas Hispanics had a trend toward more aggressive disease, although the differences we observed were modest. These differences may be related to biological factors or different treatment preferences.

Prevalence of colorectal cancer surveillance for ulcerative colitis in an integrated health care delivery system.

BACKGROUND & AIMS: The absence of grade A supporting evidence for surveillance colonoscopy in patients with ulcerative colitis (UC) has led to controversy regarding its benefit, yet it is routinely recommended in practice guidelines. Limited data are available on rates of colonoscopy surveillance and factors associated with surveillance. METHODS: A retrospective study of UC patients receiving care between 2006 and 2007 with ≥ 8 years history of UC was conducted. Primary outcome was the proportion of patients who underwent surveillance during this 2-year study period. Sociodemographic and disease factors were identified a priori from variables recorded electronically in the medical record; multivariable associations with surveillance were estimated using logistic regression. RESULTS: Of 771 patients with ≥ 8 years history of UC, 24.6% of patients underwent at least 1 surveillance colonoscopy within the 2-year study period, with a maximum of 38.5% observed among patients with primary sclerosing cholangitis. In a multivariable analysis, gender, age, race, and education were not associated with surveillance. Factors associated with increasing surveillance included lack of significant comorbidity (Charlson-Deyo index 0 vs 1+: odds ratio [OR], 1.7; 95% confidence interval: 1.1-2.5), > 3 inflammatory bowel disease-related outpatient visits (OR, 2.0; 95% CI: 1.4-3.0), and use of mesalamine (OR, 2.8; 95% CI: 1.7-4.4). CONCLUSIONS: Utilization of surveillance colonoscopy in a 2-year period was low, even among high-risk patients. Although specific factors recorded in computerized data were identified to be associated with surveillance, a greater understanding of how patients and physicians decide on surveillance is needed.

New screening guidelines for colorectal cancer: a practical guide for the primary care physician.

Until recently, most clinical guidelines in the United States were in general agreement about the tests available for colorectal cancer screening, recommending fecal occult blood tests every year, flexible sigmoidoscopy every 5 years, both these tests together, double contrast barium enema every 5 years, or colonoscopy every 10 years. However, the release of two new sets of guidelines in 2008 has made it necessary for primary care physicians to update their knowledge of the recommended screening options. The most influential factor in determining whether a patient is screened is recommendation from a physician. The primary goal of this article is to review and critique the new guidelines for average-risk screening in adults older than 50 years. Armed with this information, primary care physicians will be better educated as to the importance of offering screening to their patients, as well as the strength and weaknesses of each recommended test.

Time trends in therapies and outcomes for adult inflammatory bowel disease, Northern California, 1998-2005.

BACKGROUND & AIMS: The management of inflammatory bowel disease (IBD) has become increasingly complicated, and it is unknown whether poor outcomes (prolonged steroid use, hospitalizations, and surgery) have declined in the general population. METHODS: This multilevel study used computerized clinical data. The study comprised 2892 adults with Crohn's disease (CD) and 5895 with ulcerative colitis (UC) who received care at 16 medical centers within an integrated care organization in Northern California between 1998 and 2005. RESULTS: Time trends included (1) a shift in gastroenterology-related visits from the gastroenterology division to primary care; (2) increased use of IBD-related drugs, except for a 7% decline in use of 5-aminosalicylate in CD and no change in steroid use for CD; (3) for the prevalence of prolonged steroid exposure (120 days of continuous use), a 36% decline for CD with a 27% increase for UC; (4) declines in the hospitalization rates of 33% for CD and 29% for UC; and (5) for the surgery rate, no significant change for CD with a 50% decline for UC. CONCLUSIONS: Declines in prolonged steroid exposure and the hospitalization rate for CD and in the hospitalization and surgery rate for UC are encouraging; however, the increase in prolonged steroid exposure for UC merits concern and further investigation. The variability in care patterns observed in this study suggests lack of standardization of care and the opportunity to identify targets for quality improvement. These findings should stimulate research to quantify the effect of current trends in IBD management.

Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy.

Establishing a balance between the rapid generation of effective immunity and the production of overly exuberant or excessively prolonged responses is critical to the maintenance of the equilibrium between health and disease. The preservation of homeostasis and prevention of inappropriate activation of immunity is safeguarded by systems integrating the influences of T-cell receptor signaling, pro-inflammatory danger signals, and positive costimulatory signals on the one hand with those of several layers of both cell-intrinsic and cell-extrinsic inhibitory checkpoints on the other. Evolution has thus provided an immunological system capable of clearance of pathogens and infected cells but which generally avoids the severe collateral damage that is associated with failure to control immunity. Central tolerance to self-antigens constitutes the first line of defense against self-destruction. Because central tolerance mechanisms fail to eliminate all self-reactive immune effector cells, other immune-regulating (peripheral tolerance) mechanisms are required to prevent excessive immune responses. Dysfunction of these inhibitory pathways in terms of reduced activity can result in the unmasking of self-directed responses and a variety of autoimmune morbidities. Conversely, enhanced inhibitory activity can restrict the generation of clinically useful immunity to cancers and to chronic infectious pathogens. This may manifest not only as inhibition of immunity directed towards what are largely aberrantly or overexpressed 'self' targets on malignant cells but also additional exaggeration of inhibitory pathway activity mediated via upregulation on tumor cells or stromal tissues of the ligands for inhibitory receptors expressed by lymphocytes. The selective pressures exerted by immuno-editing will favor the outgrowth of such immuno-evasive malignant clones. These pathways therefore represent significant hurdles to the generation of therapeutic anti-cancer responses. The most active of the T-cell intrinsic inhibitory pathways belong to the immunoglobulin superfamily, which occupies a central importance in the coordination of immune responses. The CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7-1/B7-2 receptor/ligand grouping represents the archetypal example of these immune regulators. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate anti-tumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system.

Gastroenterologists' attitudes and self-reported practices regarding inflammatory bowel disease.

BACKGROUND: The purpose was to assess organization-, physician-, and patient-based aspects of inflammatory bowel disease (IBD) practice variation within an integrated care delivery system and the extent to which physicians are interested in adopting a chronic care model and/or nurse assistance to manage IBD patients. METHODS: As part of an observational cohort study to understand variation in IBD care and outcomes, we conducted semistructured, open-ended interviews with 17 gastroenterologists and 1 gastroenterology registered nurse at 6 clinics in an integrated care delivery system. Interviews were taperecorded and transcribed. We coded and analyzed transcripts using standard qualitative methods. RESULTS: Physicians reported a range of attitudes and practices regarding IBD. Analysis showed differences in 3 domains and 8 subdomains: 1) patient education and choices, including health education and patient use of complementary and alternative medicine; 2) decisions about diagnosis and treatment, including practice guidelines, conferring with colleagues, using infliximab, and medical hospitalization; and 3) organizational aspects of care, including primary care involvement with IBD and MD attitudes toward ancillary support. CONCLUSIONS: Standardized algorithms on care for IBD patients do not exist, but opportunities may exist to improve IBD care by: having initial work-ups and management of patients in remission in primary care; creating and maintaining opportunities for gastroenterologists to confer with colleagues and acknowledged local experts; and having nurse coordination for medications and labs and/or some type of specialty IBD clinic for high-need patients. This research highlights the need for more directed comparative efficacy and effectiveness trials that will serve to define preferred treatment strategies.

Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatient pharmacy dispensings.

BACKGROUND: There are few contemporary estimates of prevalence rates for inflammatory bowel disease (IBD) in diverse North American communities. METHODS: We estimated the period prevalence of IBD for January 1, 1999, through June 30, 2001, among 1.8 million randomly sampled members of nine integrated healthcare organizations in the US using computerized diagnoses and outpatient pharmaceutical dispensing. We also assessed the positive predictive value (PPV) and sensitivities of 1) the case-finding algorithm, and 2) the 30-month sampling period using medical chart review and linkage to a 78-month dataset, respectively. RESULTS: The PPV of the case-finding algorithm was 81% (95% confidence interval [CI], 78-87) and 84% (95% CI, 79-89) in two different organizations. In both, the sensitivity of the optimal algorithm, compared with the most inclusive, exceeded 90%. The sensitivity of the 30-month sampling period compared with 78 months was 61% (95% CI, 57-64) in one organization. Applying a slightly more sensitive case-finding algorithm, the average period prevalence of IBD across the nine organizations, standardized to the age- and gender-distribution of the US population, 2000 census, was 388 cases (95% CI, 378-397) per 100,000 persons (range 209-784 per 100,000; average follow-up 26 months). The prevalence of Crohn's disease, ulcerative colitis, and unspecified IBD was 129, 191, and 69 per 100,000, respectively. CONCLUSIONS: The observed average prevalence was similar to prevalence proportions reported for other North American populations (369-408 per 100,000). Additional research is needed to understand differences in the occurrence of IBD among diverse populations as well as practice variation in diagnosis and treatment of IBD.

Screening tests for colorectal cancer: a menu of options remains relevant.

Until the early 1990s, no evidence was available to show that screening for colorectal cancer (CRC) by any means actually saved lives. Subsequently, sufficient evidence for the efficacy of fecal occult blood testing (FOBT) and flexible sigmoidoscopy allowed the US Preventive Services Task Force to publish guidelines for CRC screening. Since that time the major organizations in the United States concerned with screening guidelines have recommended a menu of screening test options including FOBT, flexible sigmoidoscopy, flexible sigmoidoscopy plus FOBT, barium enema, and colonoscopy. No organization, except for the American College of Gastroenterology, has designated any one of these options as "preferred." Nevertheless, the lay press and many gastroenterology opinion leaders have encouraged Americans to have only one test--colonoscopy. In this review we discuss the rationale for caution in designating one screening test as "the best" and present information on how new stool and serum tests can be used effectively to screen for CRC.