QL535: CD2-Based PSMA T-Cell Engager Maintains Anti-Tumor Activity in Advanced Prostate Cancer Models

PSMA-targeted T-cell engagers have struggled in solid tumors because they don’t activate T cells strongly enough and the immune cells become exhausted quickly. QL535 solves this problem by adding a second co-stimulatory signal through CD2, a molecule on T cells that’s abundant in prostate cancer tumors. Researchers analyzed immune cells from 14 advanced prostate cancer patients and found CD2 was expressed more broadly and at higher levels than CD28, especially on killer T cells. This discovery led them to design QL535 as a trispecific molecule that simultaneously targets PSMA on cancer cells, engages CD3 to activate T cells, and engages CD2 for additional stimulation.

In lab tests, QL535 killed PSMA-positive cancer cells as effectively as CD28-based designs but with a major advantage: it triggered less inflammatory cytokine release. When exposed to repeated stimulation using patient immune cells, QL535 maintained its killing power longer than competing designs and showed signs of less T-cell exhaustion. This matters enormously for solid tumors where cancer cells repeatedly present themselves to immune cells over weeks and months.

In mouse models of prostate cancer using patient tumors, QL535 shrank tumors in a dose-dependent manner. Safety studies in primates showed the drug was well tolerated. After the first dose, immune markers increased temporarily but returned to normal within a week. T cells dropped initially but bounced back by day seven. Systemic exposure increased predictably with dose, suggesting a clear window for testing in humans.

The biological logic is sound: QL535 harnesses a co-stimulatory pathway that actually exists abundantly in prostate cancer tumors rather than forcing an artificial one. It maintains T-cell killing power under the chronic stimulation that characterizes the solid tumor microenvironment. Combined with its favorable tolerability profile and strong preclinical efficacy, QL535 represents a genuine step forward for men with PSMA-positive advanced disease.

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