ALBERT

Description: Postmenopausal women have an increased risk of cardiovascular disease, and heart disease is the leading cause of death in postmenopausal American women. Conventional hormone replacement therapy has been shown to result in an increase in thrombotic events in large prospective clinical trials including HERS I, and the recently halted Women’s Health Initiative. One possible mechanism for this observed increase is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory factors. An estimated 50 million American women are peri or postmenopausal and clinical therapies for menopausal symptoms remain a significant challenge in light of the known thrombotic risks. In this prospective blinded study, we examined the short-term effect of topical progesterone cream on menopausal symptom relief in 30 healthy postmenopausal women. Potential adverse effects of topical progesterone on hemostatic and inflammatory factors and cortisol levels were also examined. Subjects were randomized to first receive either 20 mg of topical progesterone cream or placebo cream for 4 weeks. Following a subsequent 4-week washout period, subjects were crossed over to either placebo cream or active drug for an additional 4-week period. In each case, progesterone and cortisol levels were monitored by salivary sampling. Baseline values, 4-week follow-up values and end-of-study values were also obtained for the Greene Climacteric Scale, total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6. For subjects receiving 20 mg of topical progesterone cream for 4 weeks, Greene Climacteric Scale scores were consistently and significantly improved (decreased) over baseline, demonstrating significant relief from menopausal symptoms. In addition, in a subpopulation of hypercortisolemic women, topical progesterone was associated with a favorable decrease in nocturnal cortisol. Surprisingly, and in sharp contrast to earlier studies with conventional hormone replacement therapy, topical progesterone had no effect on any of the hemostatic components examined: total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, and PAI-1 levels were all unchanged. Levels of CRP, TNFα and IL-6 also remained unchanged. From this study we conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.

Description: 〈span〉Mantle lithosphere heterogeneities are well documented, are ubiquitous, and have often been thought to control lithosphere-scale deformation. Here, we explore the influence of deep scarring in crustal deformation in three dimensions by considering the Ouachita orogeny in the southeastern United States, an example of a continental collision where mantle structure is present but not previously linked to the regional crustal tectonics. We present state-of-the-art continental compressional models in the presence of inherited three-dimensional lithospheric structure. Our models find that the surface expression of the Ouachita orogeny is localized by, and projected from, the controlling mantle scarring, in keeping with geological and geophysical observations. We are able to produce a large-scale arcuate orogeny with associated basin development appropriate to the Ouachita orogeny, alongside smaller-scale crustal faulting related to the region. This study offers a new and alternative hypothesis to the tectonic history of the Ouachita orogeny, with previous research having focused exclusively on crustal structures. The findings have broad implications, demonstrating the important potential role of the mantle lithosphere in controlling crustal dynamics and highlighting the requirement to consider deeper structure and processes when interpreting tectonic evolution of lithospheric-scale deformation.〈/span〉

Description: Near-surface thrust fault splays and antithetic backthrusts at the tips of major thrust fault systems can distribute slip across multiple shallow fault strands, complicating earthquake hazard analyses based on studies of surface faulting. The shallow expression of the fault strands forming the Seattle fault zone of Washington State shows the structural relationships and interactions between such fault strands. Paleoseismic studies document an ~7000 yr history of earthquakes on multiple faults within the Seattle fault zone, with some backthrusts inferred to rupture in small (M ~5.5–6.0) earthquakes at times other than during earthquakes on the main thrust faults. We interpret seismic-reflection profiles to show three main thrust faults, one of which is a blind thrust fault directly beneath downtown Seattle, and four small backthrusts within the Seattle fault zone. We then model fault slip, constrained by shallow deformation, to show that the Seattle fault forms a fault propagation fold rather than the alternatively proposed roof thrust system. Fault slip modeling shows that back-thrust ruptures driven by moderate (M ~6.5–6.7) earthquakes on the main thrust faults are consistent with the paleoseismic data. The results indicate that paleoseismic data from the back-thrust ruptures reveal the times of moderate earthquakes on the main fault system, rather than indicating smaller (M ~5.5–6.0) earthquakes involving only the backthrusts. Estimates of cumulative shortening during known Seattle fault zone earthquakes support the inference that the Seattle fault has been the major seismic hazard in the northern Cascadia forearc in the late Holocene.

Description: 〈span〉〈div〉Abstract〈/div〉Mantle lithosphere heterogeneities are well documented, are ubiquitous, and have often been thought to control lithosphere-scale deformation. Here, we explore the influence of deep scarring in crustal deformation in three dimensions by considering the Ouachita orogeny in the southeastern United States, an example of a continental collision where mantle structure is present but not previously linked to the regional crustal tectonics. We present state-of-the-art continental compressional models in the presence of inherited three-dimensional lithospheric structure. Our models find that the surface expression of the Ouachita orogeny is localized by, and projected from, the controlling mantle scarring, in keeping with geological and geophysical observations. We are able to produce a large-scale arcuate orogeny with associated basin development appropriate to the Ouachita orogeny, alongside smaller-scale crustal faulting related to the region. This study offers a new and alternative hypothesis to the tectonic history of the Ouachita orogeny, with previous research having focused exclusively on crustal structures. The findings have broad implications, demonstrating the important potential role of the mantle lithosphere in controlling crustal dynamics and highlighting the requirement to consider deeper structure and processes when interpreting tectonic evolution of lithospheric-scale deformation.〈/span〉

Description: Plate tectonic reconstructions are usually constrained by the correlation of lineaments of surface geology and crustal structures. This procedure is, however, largely dependent on and complicated by assumptions on crustal structure and thinning and the identification of the continent-ocean transition. We identify two geophysically and geometrically similar upper mantle structures in the North Atlantic and suggest that these represent remnants of the same Caledonian collision event. The identification of this structural lineament provides a sub-crustal piercing point and hence a novel opportunity to tie plate tectonic reconstructions. Further, this structure coincides with the location of some major tectonic events of the North Atlantic post-orogenic evolution such as the occurrence of the Iceland Melt Anomaly and the separation of the Jan Mayen microcontinent. We suggest that this inherited orogenic structure played a major role in the control of North Atlantic tectonic processes.

Description: The Evergreen basin is a 40-km-long, 8-km-wide Cenozoic sedimentary basin that lies mostly concealed beneath the northeastern margin of the Santa Clara Valley near the south end of San Francisco Bay (California, USA). The basin is bounded on the northeast by the strike-slip Hayward fault and an approximately parallel subsurface fault that is structurally overlain by a set of west-verging reverse-oblique faults which form the present-day southeastward extension of the Hayward fault. It is bounded on the southwest by the Silver Creek fault, a largely dormant or abandoned fault that splays from the active southern Calaveras fault. We propose that the Evergreen basin formed as a strike-slip pull-apart basin in the right step from the Silver Creek fault to the Hayward fault during a time when the Silver Creek fault served as a segment of the main route by which slip was transferred from the central California San Andreas fault to the Hayward and other East Bay faults. The dimensions and shape of the Evergreen basin, together with palinspastic reconstructions of geologic and geophysical features surrounding it, suggest that during its lifetime, the Silver Creek fault transferred a significant portion of the ~100 km of total offset accommodated by the Hayward fault, and of the 175 km of total San Andreas system offset thought to have been accommodated by the entire East Bay fault system. As shown previously, at ca. 1.5–2.5 Ma the Hayward-Calaveras connection changed from a right-step, releasing regime to a left-step, restraining regime, with the consequent effective abandonment of the Silver Creek fault. This reorganization was, perhaps, preceded by development of the previously proposed basin-bisecting Mount Misery fault, a fault that directly linked the southern end of the Hayward fault with the southern Calaveras fault during extinction of pull-apart activity. Historic seismicity indicates that slip below a depth of 5 km is mostly transferred from the Calaveras fault to the Hayward fault across the Mission seismic trend northeast of the Evergreen basin, whereas slip above a depth of 5 km is transferred through a complex zone of oblique-reverse faults along and over the northeast basin margin. However, a prominent groundwater flow barrier and related land-subsidence discontinuity coincident with the concealed Silver Creek fault, a discontinuity in the pattern of seismicity on the Calaveras fault at the Silver Creek fault intersection, and a structural sag indicative of a negative flower structure in Quaternary sediments along the southwest basin margin indicate that the Silver Creek fault has had minor ongoing slip over the past few hundred thousand years. Two earthquakes with ~M6 occurred in A.D. 1903 in the vicinity of the Silver Creek fault, but the available information is not sufficient to reliably identify them as Silver Creek fault events.

Description: Gravity and magnetic anomalies suggest that the Olympia structure beneath the southern Puget Lowland (western Washington State, U.S.) vertically displaces Eocene Crescent Formation strata. Northeast of the Olympia structure, middle Eocene Crescent Formation is beneath 4–6 km of Paleogene–Neogene and Quaternary strata of the Tacoma basin, whereas the Crescent Formation is exposed at the surface immediately to the south. Although numerous marine seismic reflection profiles have been acquired near the surface location of the Olympia structure as defined by potential field anomalies, its tectonic character remains enigmatic, in part because inlets of southern Puget Sound are too shallow for the collection of deep-penetration marine seismic profiles across the geophysical anomalies. To supplement existing shallow-marine data near the structure, we acquired 14.6 km of land-based seismic reflection data along a profile that extends from Crescent Formation exposed in the Black Hills northward across the projected surface location of the Olympia structure. The reflection seismic data image the Crescent bedrock surface to ~1 km depth beneath the southern Tacoma basin and reveal the dip on this surface to be no greater than ~10°. Although regional potential field data show a strong linear trend for the Olympia structure that implies folding over a blind thrust and/or bedrock juxtaposed against a weakly to nonmagnetic sediment section, high-resolution magnetic anomaly analysis along the land-based profile suggests that the structure is more complex. Overall, seismic and potential-field profiles presented in this study identify only minor shallow faulting within the projected surface location of the Olympia structure. We suggest that the mapped trace of the Olympia structure along the northern flank of the Black Hills, at least within the study area, is constrained by juxtaposed normal and reversely magnetized Crescent Formation units and minor tectonic deformation of Crescent Formation bedrock.

Description: Background: Talabostat (PT-100), an orally available inhibitor of dipeptidyl peptidases, is in Phase 2 studies for B-cell malignancies and solid tumors. Talabostat increases production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses (Adams S, Cancer Research, 2004;64:5471). Talabostat may thus enhance the antibody-dependent cytotoxicity of MAbs such as rituximab. Methods: This is a Phase 1 study to evaluate the safety and activity of talabostat and rituximab in patients with indolent NHL who did not respond or progressed following rituximab. Rituximab 375mg/m2 was administered weekly x 4. Total daily doses of talabostat 400μg (n=6), 600μg (n=3), or 800μg (n=6) were administered BID for 6 days following each dose of rituximab. Cytokines and chemokines were assessed pre-, 2, and 6 hours post-talabostat on Days 1, 6, 13, 20, and 27. Flow cytometry was performed at baseline and Day 28. Clinical and laboratory evaluations were performed at specified times. Adverse events (AEs) were graded per NCI-CTC and recorded throughout the study. Disease assessments were performed on Days 28 and 84. Results: 11 men and 4 women aged 48–82 with NHL (n=10) or SLL/CLL (n=5) have been treated. 9 patients completed the 28-day study: 4 at 400μg, 1 at 600μg, and 4 at 800μg. Enrollment continues at 400μg/day. The most frequent AEs have been edema (67%), nausea (47%), dizziness (40%), hypotension (33%), fatigue (33%), vomiting (33%), constipation (33%), thrombocytopenia (27%), and weight gain (27%). Grade 3 toxicities include: dizziness, myopathy (400μg/day), and 2 events of thrombocytopenia (600μg/day). Grade 3 peripheral edema, myalgia, dehydration, electrolyte imbalance, hypereosinophilia, elevated CPK (primarily CK-MM), and rhabdomyolysis were seen in 2/6 patients at 800μg/day; these events were DLTs. One partial response (PR) lasting 7 months was seen in one patient (800μg/day). A PR was seen in a second patient at 800μg/day but did not meet the strict NCI-WG criteria for response. Elevations in cytokines 〉ULN were reported across all doses following talabostat: G-CSF (13/15), IL-1β (10/15), IL-2 (7/15), IL-6 (8/15), IL-8 (8/15), IL-10 (11/15), TNF-α (11/15), and IFN-γ (3/15). At Day 28 or early termination, CD20 was decreased in most (12/15) patients. Increases were seen in the percentage of CD3 (12/15), CD3/4 (11/15) and CD3/8 (9/15). In all 5 patients with SLL/CLL, CD5+/CD20+ was

Description: Background: T cells can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In an ongoing trial of Xcellerated T Cells in subjects with chronic lymphocytic leukemia, marked and sustained reductions in lymphadenopathy and splenomegaly were observed (Wierda et al., ASCO 2004). Increases in neutrophil, platelet and NK cell counts were also documented. This study is designed to determine if similar effects can be observed in subjects with indolent non-Hodgkin’s lymphoma (NHL). Methods: Subjects must have indolent NHL (follicular, small lymphocytic, marginal zone, or mantle cell lymphoma), have relapsed or refractory disease, and have received at least 1 but not more than 4 prior treatment regimens. PBMC are collected by leukapheresis for the Xcellerate Process, and subjects subsequently receive two infusions of 20–60 x 109 Xcellerated T Cells separated by 6–8 weeks. Approximately 40 subjects will be treated. Results: Seven subjects have been enrolled and Xcellerated T Cells have been manufactured in 5 subjects to date. T cells expanded 181.8 ± 88.5 fold and the final product was 〉99.0 ± 0.0% T cells (mean + SD). One subject with small lymphocytic lymphoma has been treated with two infusions of 38.6 x 109 Xcellerated T Cells. There have been no serious adverse events to date. Following the first treatment, the lymphocyte count increased from 1.8 x 109/L to 2.9 x 109/L on Day 28. The neutrophil count also increased from 2.9 x 109/L to 5.5 x 109/L six weeks following infusion. The subject had a significant reduction in cervical lymphadenopathy and a slight decrease in bulky mesenteric lymphadenopathy six weeks following the first infusion. Conclusions: Xcellerated T Cells can be manufactured in subjects with indolent NHL. Treatment leads to significant increases in T cell and neutrophil counts. Preliminary data suggest a reduction in peripheral lymphadenopathy. Data on additional subjects will be presented.

Description: CD74, also known as HLA-DR-associated invariant chain, is a type II transmembrane glycoprotein highly expressed in many B-cell malignancies. The limited expression of CD74 in normal tissues suggests it may be a suitable ADC target for these tumor types. Accordingly, we engineered an anti-CD74 human IgG1 antibody (SP7219) using novel Fab-based ribosome display methods. The selected Fabs were readily reformatted and directly screened as IgGs using Sutro's unique high-throughput, cell-free protein synthesis platform, Xpress CFTM. We then developed novel, potent ADCs, SP7676 and SP7675 (STRO-001), comprised of our lead antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-warheads with an average drug-antibody ratios (DAR) of 2. We used site-specific conjugation technology which results in a high degree of homogeneity characterized by the drug linker covalently binding to a single defined site. The sites for conjugation were selected based on highest cell killing activity and stablity in vitro and in vivo. Both ADCs demonstrate potent cell killing activity across multiple B-cell tumor lines in vitro, and anti-tumor activity in preclinical multiple myeloma xenograft models. In vitro cytotoxicity assays show nanomolar potency of STRO-001 in four MM cell lines: Mc/CAR (IC50 0.8 nM), MM.1S (IC50 10-11 nM), U266B1 (IC50 8.5 -9.3 nM), and ARP-1 (IC50 4.3-22 nM). CD74 cell surface expression is required for ADC anti-proliferative effect but the expression level does not seem to correlate with in vitro potency. SP7676 elicited a robust anti-tumor response in the ANBL-6 multiple myeloma xenograft model. Durable regressions were observed in all mice at ≥ 3 mg/kg, with equivalent efficacy (regression) at 3 mg/kg (every 3 days x5) and 10 mg/kg (every 3 days x5 or weekly x3). SP7676 also elicited a clear survival benefit in a disseminated multiple myeloma CAG xenograft model starting at 1mg/kg every 3 days x 5 doses. Similarly, both SP7676 and STRO-001 inhibited the formation of internal visceral tumors in the ARP-1 xenograft model after 3 weekly doses of 3 mg/kg. Evaluation of our lead candidate, STRO-001 in additional MM cell lines and primary patient samples is planned. The tolerability of STRO-001 in non-human primates is under evaluation. STRO-001 was administered to cynomolgous monkeys in an exploratory dose-escalating study up to 30 mg/kg x 2 doses on Day 1 and 15. STRO-001 reduces normal B-cell populations at ≥1 mg/kg after a single dose, providing pharmacodynamic evidence of B-cell targeting while other hematopoietic lineages are mostly affected only at the highest dose studied. Anticipated hematologic toxicities were readily reversible at 1, 3 and 10 mg/kg and target organs of interest were identified. Based on these encouraging data, STRO-001 is advancing to IND-enabling studies for the treatment of CD74 expressing multiple myeloma and other B-cell malignancies. Disclosures Abrahams: Sutro Biopharma: Employment. Li:Sutro Biopharma: Employment. Yu:Sutro Biopharma: Employment. Krimm:Sutro Biopharma: Employment. Kahana:Celgene: Employment. Narla:Celgene: Employment. Schwartz:Celgene: Employment. Boylan:Celgene: Employment. Hoffmann:Sutro Biopharma: Employment. Steiner:Sutro Biopharma: Employment. Zawada:Sutro Biopharma: Employment. Stephenson:Sutro Biopharma: Employment. Bruhns:Sutro Biopharma: Employment. DeAlmeida:Sutro Biopharma: Employment. Matheny:Sutro Biopharma: Employment. Bussell:Sutro Biopharma: Employment. Galan:Sutro Biopharma: Employment. Kline:Sutro Biopharma: Employment. Vasquez:Sutro Biopharma: Employment. Yam:Sutro Biopharma: Employment. Stafford:Sutro Biopharma: Employment. Heinsohn:Sutro Biopharma: Employment. Sato:Sutro Biopharma: Employment. Molina:Sutro Biopharma: Employment. Hallam:Sutro Biopharma: Employment. Lupher:Sutro Biopharma: Employment.