IL13RA2 expression

DTriTEs exhibit potent anti-tumor effects and durable in vivo activity, offering promising therapeutic potential against GBM. These findings support further development of such multivalent therapeutic strategies to improve treatment outcomes in GBM and potentially other antigenically heterogeneous tumors. The opportunity to advance such important therapies either through biologic delivery or direct in vivo nucleic acid production is compelling.

The results of this study suggest that the expression of IL13Rα2 might be used as a potential prognostic indicator in osteosarcoma patients. Furthermore, it is observed that IL13Rα2 influences the resistance to the chemotherapeutic agent doxorubicin. Therefore, a therapeutic trial targeting IL13Rα2 might be a new therapeutic strategy for osteosarcoma, especially those highly expressing IL13Rα2.

P1, N=30, Recruiting, Yang Zhang

Widespread IL13Ra2 expression in BSG, particularly elevated in the H3F3A mutant group, was strongly correlated with H3F3A mutations, increased proliferation, and heightened tumor stemness. IL13Ra2 represents a promising therapeutic target for BSGs, potentially benefiting patients with H3K27M mutations, DIPGs, WHO Grade IV, and pontine location-specific BSGs, particularly those with H3K27M mutations.

We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein, enhancing the interaction of UBE3C and p53, thereby inducing the K48-linked ubiquitination of p53. In conclusion, the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination, adding an important layer to the connection between IL-13 and p53, which can be translated into novel targeted therapies.

Therefore, the Pep-1-Phor21-mediated targeting of IL-13Rα2 is a potentially novel therapeutic strategy for TNBC. Given that tumor cells can be selectively sensitized to Pep-1-Phor21 via the epigenetic up-regulation of IL-13Rα2, a combined adjuvant approach involving Pep-1-Phor21 and epigenetic inhibitors may be an effective strategy.

Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with Zr-oxine retain critical product attributes and suggest Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.

IL-13Rα2 expression was significantly associated with cytoplasmic distribution of FUS in human glioma samples and could be the independent prognostic factors for OS, while the prognostic value of its co-expression with cytoplasmic FUS in glioma need to be addressed in the future studies.

When IM and dysplastic gastroids (Meta3 and Meta4, respectively) were treated with either IL-13 or BSA, we observed that IL-13 treatment caused the phosphorylation of STAT6 (Fig 1C). These results suggest that IL-13 could play important roles in different stages of the stomach carcinogenesis.

ADCT-211 is an antibody-drug conjugate composed of HuCl47, a humanized IgG1 antibody directed against human IL13RA2, site-specifically conjugated using GlycoConnectTM technology to PL1801, which contains HydraspaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG2000 (drug to antibody ratio ~ 1.8). Expression of membranous IL13RA2 was confirmed by IHC in a panel of primary and refractory GBM samples and malignant melanoma, highlighting them as potential indications for the clinical development of ADCT-211. In conclusion, ADCT-211 demonstrated potent and specific in vitro and in vivo anti-tumor activity and it was stable and well tolerated in the rat, warranting further development of ADCT-211 into the clinic in IL13RA2-expressing cancers.

The highest non-severely toxic dose of LM-306 was determined to be 9 mg/kg in the DRF study and MTD was determined to be 18mg/kg in MTD study for male monkey. In summary, LM-306 showed high binding affinity to human IL13Rα2 expressing cells with potent cytotoxicity in vitro and significant in vivo inhibition of tumor growth, suggesting its therapeutic benefit in immuno-oncology.Summary of parameters of LM-106 and LM-306 binding affinity, internalization, ADCC and cytotoxicityAssayAntibody EC50 (nM)HEK293/H_IL-13Rα2U251A375SKMEL5Binding affinityLM-1060.990.210.570.1LM-3061.470.330.80.12InternalizationLM-1062.22-0.43-ADCCLM-1060.16-0.03-LM-3060.31-0.03-Cytotoxicity (IC50)LM-3060.030.050.010.005

MDNA132 is an engineered IL13Rα2 selective superkine that accumulates in TME of IL13Rα2 expressing tumors in mice. MDNA109FEAA-Fc-MDNA132 and anti-PD1-MDNA132 retain their respective receptor binding profile, IL2R agonism and PD1/PDL1 blockade illustrating the versatilityof MDNA132 BiSKIT platform for targeted delivery of a broad range of therapeutic and/or immune-modulatory agents to tumors overexpressing the IL13α2 decoy receptor.