Resolve Therapeutics (United States)

Abstract EVOLVE104 is the first CD3 T cell engager (TCE) being developed for solid tumors which utilizes integrated CD2 T cell co-stimulation. EVOLVE104 is a trispecific molecule which targets ULBP2/5/6 on the tumor cell and uses affinity-tuned CD3 engagement together with a CD2-selective fusion protein to deliver coordinated costimulatory signal integration to the T cell to optimize its effector function. ULBP2/5/6 are closely related proteins of the UL16 binding protein family which are recognized by the NKG2D receptor and induced on tumor cells while maintaining restricted expression on normal human tissues. In patient tumor samples, at both the RNA and protein level, ULBP2/5/6 expression is higher in carcinomas of squamous pathology as compared to adenocarcinomas. For example, squamous non-small cell lung cancer (NSCLC), squamous head and neck, and squamous urothelial cancer demonstrate > 70% ULBP2/5/6 positivity. In addition, transitional urothelial cancer, which encompasses most bladder cancers, also shows 70% ULBP2/5/6 positivity. We have verified that matched primary and metastatic urothelial, head and neck, and NSCLC tumors retain ULBP2/5/6 expression, and that standard of care treatments as late as post-third line do not decrease ULBP2/5/6 expression levels. These observations support the positioning of EVOLVE104 in squamous tumors and transitional urothelial cancers in initial clinical trials. Using a variety of indication-specific tumor cell lines, we show an in vitro T-cell directed cell cytotoxicity EC50 of ∼100 pM for EVOLVE104 with concomitant T cell activation, proliferation, and cytokine release. EVOLVE104 demonstrates a minimal efficacious dose of 0.25 mg/kg in indication-specific human cell line derived in vivo xenograft models in NSG mice engrafted with human PBMCs. In non-human primates, EVOLVE104 was well tolerated at doses up to 24 mg/kg, with no adverse findings or organ-specific toxicities at supra-pharmacologic levels compared to predicted human efficacious exposures. We show binding of EVOLVE104 in vivo on more than 95% of peripheral T cells for at least 168 hours post dose and no evidence for cytokine excursions throughout the duration of the study. Thus, preclinical data demonstrate safety and efficacy of EVOLVE104 and support the upcoming Phase I clinical study. EVOLVE104, a trispecific TCE with integrated affinity-tuned CD3 binding and CD2 co-stimulation, optimizes effector T cells for anti-tumor activity. The enriched expression of its tumor antigen target, ULBP2/5/6, in primary and metastatic squamous tumors and transitional bladder cancers, together with its compelling in vitro and in vivo pharmacology and nonclinical safety profile, position EVOLVE104 as a first-in-category immunotherapy to address underserved patient populations with high unmet needs. Citation Format: Oksana A. Sergeeva, Jennifer Zeiger, Colleen Brown, William DeMaria, Donal Ryan, Antonio Ward, Guixian Jin, Martin Preyer, Yanhuai Ding, Bruce Andrien, Mark Aimone, Agnes Meade, Jay S. Fine, Jeremy S. Myers, Stella Martomo. EVOLVE104, a differentiated T cell engager targeting the novel antigen ULBP2/5/6, exhibits potent preclinical efficacy for the treatment of squamous tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3519.

Ambitious biodiversity goals to protect 30% or more of the Earth’s surface by 2030 to prevent the most likely and imminent extinctions require strategic near-term targets. We propose Conservation Imperatives, spanning 164 Mha across 16,825 unprotected sites harboring rare and threatened species. These sites should be prioritized for conservation action over the next three to five years as part of a broader strategy to expand the global protected area network. The expansion of global protected areas between 2018–2023 incorporated only 7% of sites harboring range-limited and threatened species, highlighting a renewed urgency to conserve these habitats. Permanently protecting only 0.74% of land found in the tropics, where Conservation Imperatives sites are concentrated, at a cost of US$34 to $56 billion per year over the next 3-5 years, could prevent the majority of predicted near-term extinctions once adequately resourced. Multiple approaches could achieve this goal: providing rights and title to Indigenous Peoples and Local Communities (IPLCs) conserving traditional lands, government designation of new protected areas on federal and state lands; or land purchase and long-term leasing of privately held lands.

Abstract Induced myeloid leukemia cell differentiation protein (MCL1) is a member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which plays a critical role in maintaining cellular homeostasis and promoting cancer cell survival. Increased expression of MCL1 in various cancers has been associated with poor prognosis and resistance to chemotherapeutic and targeted agents. We previously described PRT1419, a novel, potent, selective MCL1 inhibitor that demonstrates anti-tumor efficacy in various preclinical models of solid and hematologic malignancies. PRT1419 is currently under evaluation in Phase I clinical trials in patients with relapsed/refractory hematologic malignancies and advanced solid tumors. To identify novel biomarkers that might predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using publicly available human cancer cell line gene dependency data generated from genome-wide CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with deleterious alterations in PBRM1 (Polybromo 1) displayed a strong dependency on MCL1. PBRM1, also known as BAF180, is a chromatin-targeting subunit of mammalian pBAF (SWI/SNF-B) complexes. PBRM1 is frequently altered in various human cancers but it has a particularly high alteration rate in ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We had previously described alterations in other mammalian SWI/SNF factors as biomarkers of MCL1 inhibitor sensitivity.We observed potent inhibition of tumor growth as well as induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not in PBRM1-WT tumor models. Depletion of PBRM1 via RNAi in PBRM1-WT ccRCC induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming PBRM1-loss cells for caspase-mediated cell death following MCL1 inhibition. Increased MCL1 activity has previously been described as a resistance mechanism to Sunitinib and Everolimus, two approved targeted agents for ccRCC. To investigate if MCL1 inhibition could potentiate the anti-tumor effects of these agents, we evaluated PRT1419 in combination with Sunitinib or Everolimus in PBRM1-loss ccRCC. PRT1419 synergized with both Sunitinib and Everolimus in inhibiting tumor growth in various models. Taken together, these findings suggest PBRM1 loss is associated with sensitivity to MCL1 inhibition in ccRCC and provide rationale for the evaluation of PRT1419 for the treatment for PBRM1-deficient ccRCC Citation Format: Norman Fultang, Brian Vidal, Ashley M. Schwab, Alexander Grego, Diane Heiser, Kris Vaddi, Neha Bhagwat, Peggy Scherle. MCL1 inhibitor PRT1419 demonstrates anti-tumor activity in PBRM1-altered clear cell renal cancer and synergizes with standard of care agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6147.

Abstract The SWI/SNF complex plays an important role in controlling gene expression via chromatin remodeling. One of its catalytic subunits, SMARCA4, is frequently mutated in multiple tumor types, and SMARCA4-deficient cells are highly dependent on the other catalytic subunit, SMARCA2, for survival. Therefore, targeting SMARCA2 with selective protein degraders has therapeutic potential in SMARCA4 deficient human cancers. We have previously described the development of a potent and selective SMARCA2 targeted degrader, PRT3789, that demonstrates robust degradation of SMARCA2 protein and excellent preclinical efficacy in SMARCA4-del models (Hulse, et al. 2022). PRT3789 will be evaluated in a Phase 1 clinical trial in patients with SMARCA4-mutant cancer. In order to assess target engagement following clinical administration of PRT3789, we developed two pharmacodynamic (PD) assays to measure SMARCA2 protein degradation and changes in SMARCA2 target gene expression in human peripheral mononuclear cells (PBMCs). We used the MSD® S-PLEX platform for the development of a sensitive and quantitative, plate-based immunoassay for determining the protein concentration of SMARCA2 in human PBMC lysates. This assay exhibits a wide dynamic range of detection for SMARCA2 with an LLOD at 1.5 pg/mL, as well as exhibiting acceptable spike recovery and minimal cross-reactivity to SMARCA4. In addition, we optimized the PBMC isolation protocol and lysis conditions to enable sensitive detection of SMARCA2 protein. In order to demonstrate downstream gene expression changes as a consequence of SMARCA2 protein degradation, we developed a secondary qPCR assay. PBMCs from healthy human donors were treated ex vivo with PRT3789 for 24 - 48 hours, followed by RNA-sequencing to identify differentially expressed genes. We refined an 8-gene panel that showed robust expression in PBMCs, as well as consistent and dose-dependent changes in response to PRT3789 treatment. We further calculated a differential gene expression (DGE) score based on expression of this gene panel that correlates with SMARCA2 protein degradation. In summary, we describe the development and characterization of two independent clinically relevant PD assays that can be used to evaluate target engagement in blood samples following PRT3789 administration. Citation Format: Andrew Moore, Carly Bachner, Lalitha Srinivasan, Pradeep Kurup, Alex Grego, Caroline Vitkovitsky, Koichi Ito, Neha Bhagwat, Peggy Scherle. Development of pharmacodynamic assays for quantifying SMARCA2 protein degradation and target gene expression in response to a SMARCA2 degrader (PRT3789) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2792.

The Global Deal for Nature (GDN) is a time-bound, science-driven plan to save the diversity and abundance of life on Earth. Pairing the GDN and the Paris Climate Agreement would avoid catastrophic climate change, conserve species, and secure essential ecosystem services. New findings give urgency to this union: Less than half of the terrestrial realm is intact, yet conserving all native ecosystems-coupled with energy transition measures-will be required to remain below a 1.5°C rise in average global temperature. The GDN targets 30% of Earth to be formally protected and an additional 20% designated as climate stabilization areas, by 2030, to stay below 1.5°C. We highlight the 67% of terrestrial ecoregions that can meet 30% protection, thereby reducing extinction threats and carbon emissions from natural reservoirs. Freshwater and marine targets included here extend the GDN to all realms and provide a pathway to ensuring a more livable biosphere.

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Non-potable and potable (principally in-direct potable) water reuse initiatives in the United States have faced increasing public opposition. Several high-profile initiatives have been halted after several years of planning and tremendous expenditures. To understand why the public holds the perceptions they do and what public participation options exist to address water reuse more constructively, a multidisciplinary analysis was undertaken by a team of social scientists, engineers, and water professionals. Through a comprehensive literature review, three in-depth case studies, and a 2-day interactive symposium this framework was developed for water professionals. The framework summarizes five underlying principles that contribute to shaping public perception and acts as a guide for water professionals in their selection of public outreach, education, and participation activities. Adhering to the principles outlined in this report contributes to building public confidence and trust, which in turn helps water utilities engage constructively with the public on challenging, contentious issues. The five principles are: Manage information for all Maintain individual motivation and demonstrate organizational commitment Promote communication and public dialog Ensure fair and sound decision making and decisions Build and maintain trust However, no checklist of “to-do's” exists for establishing public confidence and trust. Quite the opposite, this research suggests that a one-size-fits-all model cannot work because the most appropriate ways to achieve the principles can vary from case to case. Thus, the framework includes an analytical structure to assess the community in which a water reuse initiative is underway. Using diagnostic questions and analytical techniques, a comprehensive picture of the community can be generated and monitored over time. Through application of the diagnostic tools and a commitment to the principles outlined above, water professionals can build the public confidence and trust they need to engage with the public on difficult water reuse issues. ISBN: 9781843396697 (Print) ISBN: 9781780403236 (eBook)

Pitheciids are known for their frugivorous diets, but there has been no broad-scale comparison of fruit genera used by these primates that range across five geographic regions in South America. We compiled 31 fruit lists from data collected from 18 species (three Cacajao, six Callicebus, five Chiropotes, and four Pithecia) at 26 study sites in six countries. Together, these lists contained 455 plant genera from 96 families. We predicted that 1) closely related Chiropotes and Cacajao would demonstrate the greatest similarity in fruit lists; 2) pitheciids living in closer geographic proximity would have greater similarities in fruit lists; and 3) fruit genus richness would be lower in lists from forest fragments than continuous forests. Fruit genus richness was greatest for the composite Chiropotes list, even though Pithecia had the greatest overall sampling effort. We also found that the Callicebus composite fruit list had lower similarity scores in comparison with the composite food lists of the other three genera (both within and between geographic areas). Chiropotes and Pithecia showed strongest similarities in fruit lists, followed by sister taxa Chiropotes and Cacajao. Overall, pitheciids in closer proximity had more similarities in their fruit list, and this pattern was evident in the fruit lists for both Callicebus and Chiropotes. There was no difference in the number of fruit genera used by pitheciids in habitat fragments and continuous forest. Our findings demonstrate that pitheciids use a variety of fruit genera, but phylogenetic and geographic patterns in fruit use are not consistent across all pitheciid genera. This study represents the most extensive examination of pitheciid fruit consumption to date, but future research is needed to investigate the extent to which the trends in fruit genus richness noted here are attributable to habitat differences among study sites, differences in feeding ecology, or a combination of both.