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Abstract
Background Immune checkpoint inhibitors have become a standard therapeutic approach for cancer patients. Despite their impressive effects in treating solid tumors in certain clinical applications, the overall response rate (ORR) remains limited, hindering its wider use. This is at least partially attributed to inefficient biodistribution of therapeutic agents and insufficient infiltration of T cells within tumor microenvironment (TME). Therefore, methods to enhance the therapeutic effects of ICB are in high demand.
Methods In this work, we produced both murine and humanized programmed cell death protein 1 (PD-1) antibody iRGD conjugates (αPD-1-(iRGD)2) through glycoengineering and bio-orthogonal reaction. The antitumor efficacy of αPD-1-(iRGD)2 was examined in murine tumor models. Biosafety and TME modulation were evaluated with histology, flow cytometry and RNA sequencing.
Results iRGD modification largely refined the penetration of both PD-1 mAb and T cells. Besides, αPD-1-(iRGD)2 engages T cells and tumor cells thus promoting tumor elimination, which is not achievable by single agent αPD-1 or combination therapy. αPD-1-(iRGD)2 selectively engages and activates PD-1+ T cells which contains more tumor specific clusters. Systemic administration of αPD-1-(iRGD)2 elicited TME remodulation and impressive tumor growth control in various mouse tumor models with different immune infiltration characteristics, indicating αPD-1-(iRGD)2 might have broad-spectrum antitumor potential. During the regimen, no weight loss or main organ damage was observed. Furthermore, αPD-1-(iRGD)2 expands a unique population of T cells expressing stem and memory associated genes, which have been previously linked to tumor regression induced by αPD-1-IL2 conjugate (Nature 610, 161–172), so called ‘better effector’.
Conclusions In this work, we found that αPD-1-(iRGD)2 could enhance therapeutic potential for cancer treatment by simultaneously engaging T cells and tumor cells, promoting T cell infiltration and expanding a unique population of ‘better effector’ T cells. αPD-1-(iRGD)2 has the potential to be a novel and promising therapeutic approach for cancer immunotherapy.
Ethics Approval All animal experiments were approved by the Institutional Animal Care and Use Committee of Drum Tower Hospital (approval number: 2020AE01064).
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