Bronchopulmonary dysplasia (BPD) is the most common long-term pulmonary complication associated with extreme preterm birth (1). BPD is a complex lung injury syndrome caused by a combination of prenatal and postnatal insults associated with prematurity that result in altered lung development (2). A major challenge to development of adequate prevention and treatment strategies is limited understanding of BPD endotypes, which are subtypes with distinct pathobiological mechanisms (1). Moreover, characterization of the molecular landscape of late-stage human lung development and how it is affected by premature birth remains incomplete, in part owing to limited availability of human tissue samples.To address these limitations, we explored the potential of tracheal aspirate-derived mesenchymal stromal cells (MSCs) to reflect the molecular landscape of the preterm lung. Earlier reports have demonstrated that these cells are lung-resident stromal cells and can be expanded in culture (3). We applied weighted gene coexpression network analysis (WGCNA) to explore the highly dimensional gene expression space of premature tracheal aspirate-derived MSC lines (4). The gene regulatory network analysis revealed gene modules that correlated with the corrected gestational age (CGA) at MSC collection and the severity of BPD, suggesting that tracheal aspirate-derived MSC transcriptomes retain transcriptional dynamics of the preterm lung. Some of the results of this study were previously reported in the form of an abstract (5).
433 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 binds an epitope on HER2 distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2 targeting agents. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration capability in solid tumor settings. Methods: HER2 expression and activity of MT-5111 was assessed in vitro by flow cytometry and cell viability assays. Serum exposure and tolerability of MT-5111 was measured in non-human primate (NHP) studies. Results: MT-5111 effectively kills 8/9 cell lines (2 gastric) with moderate to high HER2 surface expression, as well as two additional gastric cell lines with lower HER2 expression. No cytotoxicity is observed on multiple HER2- cell lines. As a protein, MT-5111 is not a substrate of drug efflux transporters that limit efficacy of ADCs. MT-5111 demonstrates effective cell-killing in vitro against cell lines expressing HER2 but resistant to trastuzumab (HCC1954) or T-DM1 (JIMT-1 and gastric SNU-216), highlighting the benefit of a novel mechanism of action to treat resistant disease. MT-5111 binds human and NHP HER2 protein. Based on serum exposure of MT-5111 in NHPs used to model pharmacokinetics, planned MT-5111 dosing in humans is above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 has a short half-life that, while allowing for efficient tumor cell targeting, minimizes serum exposure to avoid systemic effects over time. Conclusions: A Phase 1, first in human, open-label dose escalation and expansion study of MT-5111 (NCT04029922) in subjects with HER2+ solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. MT-5111 represents a novel HER2 targeted therapy for patients with HER2+ cancers with potential to overcome mechanisms of tumor resistance to existing therapies.
Engineered toxin bodies (ETBs) are differentiated, targeted therapeutics comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLTA) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration features in the solid tumor settings. MT-5111 has been designed to bind a HER2 domain distinct from the trastuzumab and pertuzumab binding sites and retains binding to HER2 and cell-kill activity even in the presence of these monoclonal antibodies. As such, MT-5111 may have the potential to be combined with other HER2 targeted therapies. MT-5111 specifically binds and kills HER2 expressing cells in a manner consistent with SLTA-mediated cellular cytotoxicity. MT-5111 effectively killed eight of nine cell lines with moderate to high HER2 surface expression, five of which were breast cancer cell lines. No cytotoxicity was observed on multiple HER2-negative cell lines at MT-5111 levels >500 fold higher than IC50 levels in HER2-positive cells. The cytotoxic activity of MT-5111 (picomolar range) is dependent on the presence of the HER2 receptor, and efficient killing is observed prior to receptor saturation. As a large molecule protein, MT-5111 is not a substrate of drug efflux transporters such as MDR1 which has been demonstrated to be one of the primary mechanisms of resistance to the antibody drug conjugate T-DM1. Specifically, T-DM1 resistant cell lines with moderate HER2 expression (JIMT-1 breast cancer and SNU-216 gastric cancer lines) were sensitive to MT-5111 but were not effectively killed by T-DM1, highlighting the benefit of a novel MOA to treat resistant disease. Further, MT-5111 has demonstrated effective cell-killing in vitro against trastuzumab resistant cell lines (HCC1954 breast cancer). MT-5111 binds both human and cynomolgus monkey HER2 protein similarly. From repeat dose studies in non-human primates, the serum exposure of MT-5111 was used to model the pharmacokinetics of MT-5111 dosing in human. This modelling suggests that MT-5111 can be administered at doses in humans above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 was designed to achieve a short half-life to allow for efficient tumor cell targeting but minimal serum exposure time to avoid systemic effects over time. This short half-life was confirmed in primates (t1/2 of ~2 to 5 hours). A Phase 1, first in human, open-label dose escalation, and expansion study of MT-5111 (NCT04029922) in subjects with HER2-positive solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. In conclusion, MT-5111 represents a novel HER2 targeted therapy which could provide benefit in subjects with HER2-positive cancers and potentially overcome mechanisms of tumor resistance to existing HER2 targeted therapies. Citation Format: Jack P Higgins, Asis Sarkar, Eric T Williams, Aimee Iberg, Roger Waltzman, Erin K Willert. MT-5111, a novel HER2 targeting engineered toxin body, under clinical development to overcome mechanisms of resistance to existing HER2 targeted therapies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-35.
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