IL13RA2 expression

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.

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

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.

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.