Intarcia Therapeutics (United States)

BackgroundPrevious studies have reported that differences in IgG and T cell responses between SARS-CoV-2 naïve and previously infected patients diminish after two vaccine doses. Yet, long-term data beyond one year and after three vaccinations is limited, with the lack of information on the impact of breakthrough infections.Methods108 health care workers (HCWs) from a Swedish Infectious Diseases University Clinic were included. IgG antibodies against the receptor-binding domain (RBD) and nucleocapsid (N) were measured along with cytokine-induced T cell responses (IFN-γ, IL-2, TNF-α) using an in-house assay. Samples were collected before (PreDX) and one month after (PDX) each dose of the mRNA Pfizer-BioNTech COVID-19 vaccine, from January 2021 until December 2022. Eligible HCWs underwent PCR-testing when showing SARS-CoV-2 associated symptoms. Breakthrough infection was identified by a positive PCR/antigen test or as in the N-IgG seroconversion post-vaccinations. Mean concentrations were compared between groups after adjustment for age and sex, using mixed model.ResultsIn total, 34 HCWs (32%) were infected prior to vaccinations. Breakthrough infections were initially few, but increased rapidly from December 2021, with 77% of the HCWs discovered with a breakthrough infection one year later (Tabel 1, Fig 1).Infected HCWs, including those previously SARS-CoV-2 naïve with breakthrough infections, consistently had higher RBD-IgG concentrations than uninfected, except from PD3 (Figure 2). Significant differences in IFN-γ were noted at all time points except PD3 and PD4. Significant differences in IL-2 was only observed within the first month, and in TNF-α at PreD4 (Figure 2).Those with breakthrough infections had significant higher RBD-IgG concentrations at all measured time points (PD3-PD4), with a similar pattern in IFN- γ, except from PD4.ConclusionDifferences in cellular and humoral immune responses to SARS-CoV-2 between infected and naïve individuals remain significant up to 23 months post-vaccination, when considering breakthrough infections.DisclosuresAll Authors: No reported disclosures

Abstract Background GB-0669 is a novel half-life extended monoclonal antibody for the prophylaxis of SARS-CoV2 infection and is one of the first biologics designed using artificial intelligence/machine learning to reach clinical development and the first against SARS-CoV2. GB-0669 targets the previously undruggable S2 domain of the SARS-CoV2 spike protein, which contains the fusion peptide and stem-helix peptides, and was selected because the S2 domain is conserved across all SARS-CoV2 variants to-date. The S2 domain is not immunodominant and is therefore not subject to selective pressure from natural infection or vaccine induced immunity. This suggesting GB-0669 will maintain its activity, unlike monoclonal antibodies directed against the SARS-CoV2 receptor-binding domain. GB-0669 is also able to neutralize other sarbecoviruses, such as SARS-CoV2 and WIV1 (Table).Table:GB-0669 EC50 against SARS-CoV2 variants and other sarbecoviruses in a VSV pseudoneutralisation assay Methods In this single-ascending dose study, healthy volunteers aged 18–55 years were administered either GB-0669 or placebo intravenously. There were five sequential dosing cohorts 100 mg, 300 mg, 600 mg, 1200 mg, 2400 mg and each cohort was randomized to receive either GB-0669 or placebo in ratios of 3:3, 3:3, 10:3, 10:3, 10:3 respectively. Total follow-up will be 43 weeks; although dosing is now complete, follow-up is ongoing.Figure:Simulated GB-0669 drug concentrations over 43 weeks (plasma and lung) following a single dose of 1200 mg Results No dose-limiting toxicity has been observed to date and all treatment-related adverse reactions observed were mild (grade 1 or 2) at all doses. Preliminary pharmacokinetic data shows dose-proportionality up to 2400 mg the highest dose tested, with a half-life of approximately 70 days. An exploratory analysis of live virus neutralization shows a clear dose response and separation from placebo at 600 and 1200 mg. Limited anti-drug antibodies were observed in a few participants, but had no observable impact on PK or viral neutralization titers. Simulated PK of GB-0669 confirmed with observed data (assuming 10% lung penetration) are at levels anticipated to protect against COVID-19 for at least 150 days (Figure). Conclusion The preliminary data support the hypothesis that GB-0669 will be able to provide a six-month duration of prophylactic efficacy against currently circulating viral variants when administered as part of a combination. Disclosures Dinesh De Alwis, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Iñaki F. Troconiz, Pharmacy, Generate Biomedicines: Advisor/Consultant Daria Hazuda, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Gavin CKW Koh, PhD, AstraZeneca: Stocks/Bonds (Public Company)|Generate:Biomedicines: Stocks/Bonds (Private Company)|GlaxoSmithKline: Stocks/Bonds (Public Company) Alexandra Snyder, MD, Generate Biomedicines: employee

Abstract Background The elderly and immunocompromised remain at high risk of severe COVID-19 due to suboptimal immune responses. Monoclonal antibodies to SARS-CoV-2 spike were highly effective for both prophylaxis and treatment, but quickly became ineffective due to viral escape. Using a machine learning-guided optimization approach, we identified two antibodies against highly conserved epitopes, one targeting the spike S2 stem helix (GB-0669) and the other against the class 4 RBD site on S1 (PRO-37587) with the goal of developing a combination for prophylaxis that would be less susceptible to viral escape. Methods GB-0669 and PRO-37587 were characterized for breadth through binding and neutralization assays against a panel of SARS-CoV-2 variants and related sarbecoviruses. We also assessed the barrier to resistance, both individually and in combination using SARS-CoV-2 Omicron BA.1 in live virus escape studies in Vero E6 cells. Passaged viruses were sequenced and assessed for viral replication. The prevalence of any observed mutations was analyzed for conservation in the SARS-CoV-2 lineages and across the sarbecovirus family. Results Both antibodies exhibited potent neutralization across SARS-CoV-2 variants including those that had not yet emerged during development of our antibodies, while displaying activity against non-SARS-CoV-2 viruses. During passage with BA.1, escape from GB-0669 was observed in passage 3 (H1156Y), while escape from PRO-37587 emerged in passage 10 through two mutations (P381S, D402G) that impaired viral replication. By the end of passage 10, neither complete nor partial escape were observed for the combination of GB-0669 and PRO-37587. These escape mutations were observed in fewer than 1% of circulating variants from the beginning of the pandemic, probably due to low selective pressure and/or their impact on viral replication. With the exception of P381S, these mutations were not observed across a range of sarbecoviruses. Conclusion We demonstrate that the combination of GB-0669 and PRO-37587 has potent and broad neutralization activity. The robust viral escape profile and conservation of these epitopes suggest that this combination is more likely to remain effective in the face of ongoing viral evolution. Disclosures Alex Ramos, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Alan Leung, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Brett T. Hannigan, PhD, Generate Biomedicines: Employee|Generate Biomedicines: Stocks/Bonds (Private Company) Adam Root, MS, MBA, Generate Biomedicines: Grant/Research Support|Generate Biomedicines: Stocks/Bonds (Private Company) Heather A. Van Epps, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Kristen Hopson, Ph.D., Generate Biomedicines: Stocks/Bonds (Private Company) Gevorg Grigoryan, PhD, Generate Biomedicines, Inc.: Employee and shareholder|Generate Biomedicines, Inc.: Stocks/Bonds (Private Company) Gavin CKW Koh, PhD, AstraZeneca: Stocks/Bonds (Public Company)|Generate:Biomedicines: Stocks/Bonds (Private Company)|GlaxoSmithKline: Stocks/Bonds (Public Company) Daria Hazuda, PhD, Generate Biomedicines: Stocks/Bonds (Private Company)

Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)-encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12-MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein-specific immune responses in mice. Specifically, the benefits of IL-12-MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12-MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

Abstract Antibody-drug conjugates (ADC) are a type of the fastest growing anticancer drug modalities. However, the traditional ADC technologies constrain on therapeutic development, requiring overexpressed targets, high internalizing antigens and efficient intracellular processing. To this end, MediLink’s TMALIN platform was developed, with an irreversible pyrimidine coupling anchor and a valyl dipropyl-lysyl glycinamide-methylene (-VK*G-NHCH2-O-) cleavable sequence. The TMALIN platform is featured as a high hydrophilicity linker-payload, remarkable stability in circulation, coupled with an efficient payload release mechanism which is achieved through the cleavage both extracellularly in the tumor microenvironment and intracellularly within lysosomes. A site-specific and homogeneous conjugation using TMALIN platform provides highly stable ADC in circulation. It is evidenced by less than 2% payload drop-off after a 21-day incubation in plasma under physiological conditions in vitro. This feature is observed in over 7 ADCs developed using the TMALIN platform. Additionally, the high stability was also illustrated by the pharmacokinetic profiles in NHP studies and clinical trials, with the overlapped curves of ADC and TAb in all TMALIN platform-based ADCs. Apart from the stability, a battery of in vitro and in vivo studies showed the linker-payload efficiently releases the payload in both tumor cells and the tumor microenvironment. Due to the high stability in circulation and efficient cleavage within tumors, the TMALIN platform ADCs have shown promising efficacy and good safety windows in preclinical studies. In xenograft mouse models, including those with low antigen expression, these ADCs have demonstrated tumor regressions and good tolerability. This highlights the potential of the TMALIN platform in improving the efficacy of ADCs and expanding their therapeutic applications. Furthermore, favorable safety profiles have been observed in clinical trials and/or pivotal non-human primate (NHP) studies for ADCs developed using the TMALIN platform. No drug-related adverse effects in organs were identified including the lungs, liver, or kidneys for those ADCs. In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. This enables the advancement of ADC development, and has the potential to expand the field of ADC therapy and improve patient outcomes. Citation Format: Tongtong Xue, Liang Xiao, Qigang Liu, Shuai Song, Ailin Shan, Xiaozhou Zhang, Sasha Stann, Jiaqiang Cai. MediLink’s TMALIN ADC linker technology: Tumor microenvironment specific extracellular and intracellular double cleavage mechanism for better efficacy and expanded target space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4702.

Abstract Introduction: Diffuse gastric cancer (DGC) accounts for one third of gastric cancers and is associated with poor differentiation, discohesive growth, chemoresistance, and worse survival compared to intestinal-type tumors. DGC is typically genomically stable, and there are no approved DGC-targeted therapies. Recent studies have identified a potential tumor-promoting role for Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif (YAP/TAZ), which interact with TEAD transcription factors to regulate gene expression. Therefore, we evaluated the activity and mechanism of TEAD inhibitors in DGC preclinical models. Methods: Gastric cancer patient-derived organoids (PDOs) and cell lines were treated with TEAD inhibitors (K-975, VT103, VT104, VT107) and/or 5-fluorouracil (5-FU) for in vitro assays evaluating cell proliferation or invasion. Additional experiments were conducted to test the in vivo activity of TEAD inhibitors or shRNA-mediated knockdown of YAP in subcutaneous xenograft, orthotopic xenograft, and lung metastasis models using a genetically engineered mouse model of gastric cancer driven by oncogenic KrasG12D and loss of Trp53/Cdh1. Results: TEAD inhibitors K-975, VT103, VT104, and VT107 reduced proliferation, colony formation, and invasion in DGC cell lines and PDOs. We observed no effect of TEAD inhibitors on the viability of normal gastric organoids. Combining the TEAD1-selective inhibitor VT103 with 5-FU chemotherapy resulted in further reduction of DGC PDO viability relative to monotherapy, including in a PDO derived from a patient with locally advanced DGC that demonstrated intrinsic resistance to neoadjuvant chemotherapy. In flank tumors and orthotopic models, inhibition of the YAP/TAZ-TEAD pathway using YAP shRNA and VT103, either alone or in combination with 5-FU, abrogated primary tumor formation, with the strongest inhibition observed with combination treatment. Loss of YAP or VT103 treatment also significantly reduced lung metastasis after tail vein injection of mouse gastric cancer cells. We hypothesized that TEAD inhibition blocks an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Consistent with this hypothesis, TEAD1 inhibition with VT103 or YAP knockdown reduced expression of the CSC marker CD44 in vitro and decreased expression of CD44 and the EMT marker Slug in tumor xenografts. Conclusions: The YAP/TAZ-TEAD pathway is an important driver of gastric cancer growth and metastasis, particularly in DGC where it may promote EMT and cancer stemness. TEAD inhibition reduces gastric cancer growth and invasion in vitro and in vivo in preclinical models and demonstrates synergistic activity with 5-FU chemotherapy. These results suggest a potential role for evaluating the efficacy of TEAD inhibitors in patients with DGC. Citation Format: Anastasiia Bulakhova, Jin Sun Cho, Jack T. Rifkin, Jaewon Kim, Thomas J. Ryan, Tracy T. Tang, Ryan H. Moy. Targeting the YAP/TAZ-TEAD pathway with TEAD inhibitors synergizes with chemotherapy and blocks diffuse gastric cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7281.

YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRASG12C-selective inhibitor treatment of KRASG12C-mutant cancers. See related commentary by Johnson and Haigis, p. 4005.

The intestinal epithelial receptor Guanylyl Cyclase C (GUCY2C) is a tumor-associated cell surface antigen expressed across gastrointestinal malignancies that can serve as an efficacious target for colorectal cancer immunotherapy. Here, we describe a yeast surface-display approach combined with an orthogonal peptide-based mapping strategy to identify the GUCY2C binding epitope of a novel anti-GUCY2CxCD3 bispecific antibody (BsAb) that recently advanced into the clinic for the treatment of cancer. The target epitope was localized to the N-terminal helix H2 of human GUCY2C, which enabled the determination of the crystal structure of the minimal GUCY2C epitope in complex with the anti-GUCY2C antibody domain. To understand if this minimal epitope covers the entire antibody binding region and to investigate the impact of epitope position on the antibody’s activity, we further determined the structure of this interaction in the context of the full-length extracellular domain (ECD) of GUCY2C. We found that this epitope is positioned on the protruding membrane-distal helical region of GUCY2C and that its specific location on the surface of GUCY2C dictates the close spatial proximity of the two antigen arms in a diabody arrangement essential to the tumor killing activity of GUCY2CxCD3 BsAb.