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Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

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dc.contributor.authorJung, K-
dc.contributor.authorYoo, S-
dc.contributor.authorKim, JE-
dc.contributor.authorKim, W-
dc.contributor.authorKim, YS-
dc.date.accessioned2023-02-21T04:33:38Z-
dc.date.available2023-02-21T04:33:38Z-
dc.date.issued2022-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/24680-
dc.description.abstractTumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K (D)) mainly varying in their dissociation rates (k (off)) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K (D) = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K (D) = 0.54 or 46 nM) due to the slow k (off) from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K (D) = 130 nM) and a faster k (off). The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4(+) and CD8(+) T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.-
dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHAntibodies-
dc.subject.MESHAntigens, Neoplasm-
dc.subject.MESHCD8-Positive T-Lymphocytes-
dc.subject.MESHColonic Neoplasms-
dc.subject.MESHCytokines-
dc.subject.MESHInterleukin-12-
dc.subject.MESHMice-
dc.subject.MESHReceptor, ErbB-2-
dc.subject.MESHTrastuzumab-
dc.subject.MESHTumor Microenvironment-
dc.titleImproved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy-
dc.typeArticle-
dc.identifier.pmid36405748-
dc.identifier.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9667294-
dc.subject.keywordbinding kinetics-
dc.subject.keywordIL12-
dc.subject.keywordimmunocytokine-
dc.subject.keywordsolid tumor-
dc.subject.keywordT cell activation-
dc.subject.keywordtumor penetration-
dc.contributor.affiliatedAuthorJung, K-
dc.type.localJournal Papers-
dc.identifier.doi10.3389/fimmu.2022.1034774-
dc.citation.titleFrontiers in immunology-
dc.citation.volume13-
dc.citation.date2022-
dc.citation.startPage1034774-
dc.citation.endPage1034774-
dc.identifier.bibliographicCitationFrontiers in immunology, 13. : 1034774-1034774, 2022-
dc.identifier.eissn1664-3224-
dc.relation.journalidJ016643224-
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Journal Papers > Hospital > Clinical Trial Center
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