Neoleukin Therapeutics (United States)

BackgroundCTM103 is an LNP mRNA encoding an IL2Rβγ selective IL-2v derivative fused with Human Serum Album. Preclinically, the novel LNP mRNA platform allowed expression and therefore extended plasma half-life of IL2v in animal models, which is not achieved with other protein-based IL-2 drugs. CTM103 stimulated significant and sustained expansion of CD8 T cells with minimal expansion of regulatory T cells and demonstrated superior efficacy than IL-2 based drugs in multiple cancer models. Therefore, the novel design of CTM103 has the potential to fully unleash the antitumor effects of the IL-2 pathway while mitigating unwanted toxicity.MethodsThis first-in-human, open label phase 1 study evaluates the safety, tolerability, and initial efficacy of CTM103 with or without pembrolizumab in patients with advanced solid tumors. The design includes two portions of the study: Parts A, CTM103 monotherapy in which patients receive intravenous CTM103 once every 3 weeks (Q3W) and Part B in which patients receive CTM103 in combination with pembrolizumab (200 mg on day 1), both intravenous Q3W. Both portions consist of 3+3 escalation cohorts to define maximum tolerated dose (MTD). If response signal is observed in a given indication and dose cohort, additional 10–20 patients will be enrolled to further evaluate the safety and efficacy.ResultsIn Part A, 9 patients in three dose cohorts received CTM103. All patients demonstrated high and prolonged plasma level of IL-2, and remarkable elevation of CD8 T cells (upto 5 folds) and NK cells (upto 25 folds). No dose-limiting toxicities (DLT) were observed. In Part B, 19 patients in two dose cohorts were enrolled, 13 of which are 1L advanced NSCLC. All patients showed increased CD8 T cells (upto 12 folds) and NK cells (upto 22 folds), and most AEs were at grade 1–2 and were mostly transient. At the cut-off date (9.9.2024), 10 of the 1L NSCLC patients reached at least one tumor evaluation time-point, 8/10 of which were evaluated to be PR (ORR=80%), including 5/7with TPS>50%, 2/2 with TPS=1–49% and 1/1 with TPS<1%.ConclusionsCTM103 was generally well tolerated at the current dose level, which already demonstrated high and prolonged plasma level of IL-2, and robust immune stimulatory activity in promoting CD8 T cells and NK cells proliferation. Initial signs of antitumor efficacy were seen in combination with pembrolizumab, regardless of PDL-1 expression level.Trial RegistrationClinicalTrials.gov ID NCT05978102.

This paper describes an unconventional way to use wav2vec 2.0 representations for voice conversion (VC) purpose. Our experiment shows that aggregate of hidden representations from wav2vec 2.0 layers is more effective in VC than using last-layer representation only. In particular, the aggregate of all hidden representations is dependent on a mainly required characteristic (e.g. vocal or linguistic) by a speech task—but such results are consistent on different datasets for the same task. Based on these results, we propose Wav2vec-VC that uses wav2vec 2.0 hidden-layer representations as input to the disentanglement-based VC. Given a target (/source) utterance, Wav2vec-VC gets an aggregated hidden representation weighted in order to perform the speaker (/content)-related tasks, and feeds it to a speaker (/content) encoder whose output is combined at a decoder to synthesize a voice-converted utterance. Our evaluation shows that Wav2vec-VC outperforms SOTA VC models in terms of both voice similarity and speech intelligibility.

Abstract KRAS mutations are highly prevalent across many different cancer types. Recent advancements in KRAS-targeted drugs, such as the FDA-approved KRAS(G12C) inhibitors sotorasib and adagrasib for NSCLC patients, have shown great promise in the clinic. Nonetheless, these new agents fail to address other mutations, such as KRAS(G12D), which overall is the most common KRAS mutation in cancers, being found in 37% of pancreatic ductal adenocarcinomas, 12.5% of colorectal cancers and 4.9% of lung adenocarcinomas. Recently, MRTX1133 has been described as a selective, non-covalent inhibitor of KRAS(G12D) that shows promising preclinical efficacy and is undergoing clinical testing. However, based on prior clinical experience with sotorasib and adagrasib, acquired resistance to MRTX1133 may reasonably be anticipated. In fact, we find that KRAS(G12D)-mutated cell lines and a patient-derived organoid model exhibit varying degrees of inherent resistance to MRTX1133. To examine the consequences of blocking KRAS signaling, we employed a KRAS(G12D)-specific PROTAC, which simulated the effects of KRAS deletion. This demonstrated that receptor tyrosine kinase (RTK) activation could compensate for loss of KRAS signaling and was a key de novo resistance mechanism. This suggests that combination therapies may need to be individually tailored to treat patients resistant to KRAS(G12D)-targeted therapies. Additionally, we developed MRTX1133 resistant cells by culturing sensitive AsPC-1 pancreatic cancer cells in gradually increasing concentrations of the inhibitor. The resulting resistant cells displayed a complex RTK activation profile compared to parental cells. To counteract this, we employed KRAS(G12D)-CHAMP RNK08179, a hetero-bifunctional small molecule agent that simultaneously targets both KRAS(G12D) and HSP90, an RTK-regulating chaperone protein. RNK08179 effectively suppressed both KRAS signaling and RTK activation in MRTX1133-resistant cancer models, overcoming the compensatory resistance mechanisms observed with MRTX1133 alone. These findings highlight the potential of KRAS-CHAMPs as a novel, effective treatment strategy for KRAS-driven cancers, particularly those resistant to KRAS(G12D) inhibitors. Citation Format: Ines Pulido Endrino, Laura gunder, Qiyue Luan, Chenghao Ying, Zimo Yang, Jinhua Li, Yaya Wang, Yuetong Sun, Chuhe Liu, Yan Dai, Haoxin Zhou, Malek Massad, Ian Papautsky, Thomas L. Prince, Guoqiang Wang, Kevin P. Foley, Weiwen Ying. Overcoming acquired resistance to KRAS(G12D) inhibition using a KRAS-HSP90 hetero-bifunctional small molecule therapeutic agent [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 1932.

BackgroundPreviously we have shown that intratumoral injection of IACS8803, a potent synthetic agonist of the Stimulator of Interferon Genes (STING) innate immune sensor, can act as an ‘in-situ vaccine’ that orchestrates a proinflammatory rewiring of the immunosuppressive myeloid stroma thereby driving robust T cell activation and infiltration into otherwise ‘cold’ tumors. While this approach promotes cure of numerous murine models, clinical application of STING agonists has been limited by IR-guided direct injection into single tumor lesions, an invasive practice with limited potential for re-administration which has failed to significantly benefit metastatic cancer patients. Immune-Stimulating Antibody Conjugates (ISACs) leverage the specificity and safety of traditional antibody-drug conjugates but carry immuno-stimulatory payloads rather than cytotoxic warheads.MethodsWith ImmunoGenesis and Silverback, Inc. we developed an ISAC using our highly potent STING agonist IACS8803 conjugated to the Her2/neu antibody trastuzumab. We characterized the specificity and uptake of this ISAC by Her2-expressing tumor cells, and the capacity of associated PBMC for downstream STING activation using ELISA or a THP1-dual reporter assay. Next, in the MT4-LA orthotopic Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx-Cre (‘KPC’) derived model of pancreatic ductal adenocarcinoma (PDAC), we compared the ability of intratumorally-administered IACS-8803 to intraperitoneally administered Her2-IACS8803 to sensitise PDAC to checkpoint blockade using bioluminescent in vivo imaging and multi-parameter flow cytometry of tumor stroma post-therapy. We also assessed their toxicity and tolerability with multiple low-dose treatments.ResultsIn mT4-LA cells expressing Her2 protein, fluorophore-conjugated Her2-IACS8803 ISAC was taken up readily using receptor-mediated endocytosis across a concentration gradient. In tumor and human PBMC coculture assays we observed an elevated expression of downstream STING pathway targets such as type I IFNs and cytokines such as CXCL10, TNFα etc. Next, in the multi-focal mT4-LA PDAC tumor model (orthotopic and flank tumors), we found that systemic administration of a low concentration of the Her2-IACS8803 ISAC could provide equivalent tumor control and survival extension to multiple intra-tumoral injections of the STING agonist in combination with immune checkpoint blockade. Finally, TIL analyses of multiparameter flow cytometry data show a proinflammatory remodeling of the myeloid stroma and enhanced T cell function as salient features of synthetic agonists in orchestrating the in vivo therapeutic benefit, an effect that mirrors intratumoral IACS-8803 delivery.ConclusionsThese preclinical studies demonstrate the potential of STING agonist ‘payloaded’, tumor-targeted antibodies non-invasively administered to provide better control of aggressive and multifocal PDAC in combination with immune checkpoint blockade.

The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.

Synthetic biology has allowed for the industrial production of supply-limited sesquiterpenoids such as the antimalarial drug artemisinin and β-farnesene. One of the only unmodified animal products used in medicine is squalene, a triterpenoid derived from shark liver oil, which when formulated into an emulsion is used as a vaccine adjuvant to enhance immune responses in licensed vaccines. However, overfishing is depleting deep-sea shark populations, leading to potential supply problems for squalene. We chemically generated over 20 squalene analogues from fermentation-derived β-farnesene and evaluated adjuvant activity of the emulsified compounds compared to shark squalene emulsion. By employing a desirability function approach that incorporated multiple immune readouts, we identified analogues with enhanced, equivalent, or decreased adjuvant activity compared to shark squalene emulsion. Availability of a library of structurally related analogues allowed elucidation of structure-function relationships. Thus, combining industrial synthetic biology with chemistry and immunology enabled generation of sustainable terpenoid-based vaccine adjuvants comparable to current shark squalene-based adjuvants while illuminating structural properties important for adjuvant activity.

BackgroundPlatelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).MethodsWe used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays.ResultsFifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0–48h and CMAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls.ConclusionsChildren tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.

BackgroundSBT6290 is a novel therapeutic comprised of a selective TLR8 agonist conjugated to a Nectin-4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells. Nectin-4 is a cell surface adhesion molecule that is overexpressed in multiple solid tumor types including triple negative breast, head and neck, lung, and urothelial cancers, with limited expression in normal tissues. Many solid tumors, including those expressing Nectin-4, are resistant to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors, however, are often replete with myeloid cells. Activation of these cells has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. TLR8 is highly expressed in myeloid cell types prevalent in human tumors, including conventional DCs and macrophages. Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells, and the priming of CTL responses. Here, we show that SBT6290 potently activates human myeloid cells in a Nectin-4-dependent manner and that a mouse surrogate confers single agent anti-tumor activity in preclinical studies. These data support the development of SBT6290 for the treatment of patients with Nectin-4-expressing tumors.MethodsSBT6290 activity was characterized in vitro using co-culture systems consisting of human immune cells and Nectin-4-expressing tumor cells. The in vivo efficacy of the SBT6290 surrogate was evaluated as a single agent in mouse tumor models expressing Nectin-4.ResultsStudies with human immune cells show that SBT6290 potently induces multiple anti-tumor immune activities including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. This activity requires the presence of Nectin-4 expressing tumor cells and the engagement of Fc gamma receptors on the surface of the myeloid cells by the conjugate to facilitate delivery of SBT6290 into myeloid cells. Notably, SBT6290 is >100 fold more potent than the free, unconjugated TLR8 agonist. Systemic administration of a SBT6290 surrogate in mice results in robust single agent efficacy in tumor models intrinsically resistant to checkpoint blockade, including the EMT6 model engineered to express human Nectin-4.ConclusionsThe preclinical data described here show the potential for SBT6290 to drive robust, single agent anti-tumor responses and support the clinical development of SBT6290 for patients with Nectin-4 expressing tumors.