A STEAP1 ADC That May Turn Tumour Killing Into an Immune Response

A newly published study has introduced an interesting variation on antibody-drug conjugates (ADCs) for advanced prostate cancer: instead of simply delivering a toxic payload to cancer cells, the treatment is designed to help the immune system recognise what remains.

The experimental ADC targets STEAP1, a cell-surface protein highly expressed in prostate cancer and already being investigated through ADCs, bispecific T-cell engagers, CAR-T cells and other approaches. Researchers used vandortuzumab, an antibody previously tested clinically against STEAP1, and compared ADCs carrying three different payloads: MMAE, DXd and the topoisomerase-I inhibitor exatecan. All three constructs had a relatively high drug-to-antibody ratio of approximately 7–8.

The exatecan version emerged as particularly interesting because its activity went beyond direct cytotoxicity. The ADC retained the antibody’s ability to engage Fc receptors on immune cells. Macrophages could engulf treated cancer cells, process their tumour antigens and present them to T cells. Both exatecan and DXd ADCs generated substantially stronger T-cell activation than the MMAE construct, while disabling Fc-receptor engagement markedly reduced this effect.

There was another potentially important feature: the topoisomerase-I ADCs produced a strong “bystander effect”. When STEAP1-positive prostate cancer cells were mixed with STEAP1-low cells, vandortuzumab-exatecan and vandortuzumab-DXd produced near-complete killing of the antigen-low population as well. This could matter because advanced prostate cancers are heterogeneous and individual metastases may express very different amounts of a therapeutic target.

The researchers also tested vandortuzumab-exatecan in a mouse model designed to reproduce one of prostate cancer’s most important clinical environments: bone metastases. Four doses of 4 mg/kg produced tumour stabilisation or regression, whereas tumours progressed in control animals.

Perhaps the most provocative result came from immunocompetent mice. Treatment produced durable tumour regression, after which the animals were challenged again with cancer cells. The acquired immunity protected them even against tumour cells lacking STEAP1. This suggests that killing STEAP1-positive cells had exposed additional tumour antigens to the immune system, producing a broader adaptive immune response, a phenomenon known as epitope spreading.

That observation is particularly interesting because the investigators also saw STEAP1 expression fall following treatment, exactly the sort of antigen loss that could eventually allow cancer to escape a targeted therapy. An immune response capable of recognising additional tumour antigens might therefore continue attacking cells even after the original STEAP1 target disappears.

The new work suggests an important direction for the next generation of ADCs. Instead of viewing an ADC simply as a guided delivery system for chemotherapy, its antibody, linker and payload could be selected to simultaneously kill cancer cells, attack neighbouring antigen-low cells and turn the resulting tumour debris into material for an adaptive immune response.

Source.