|Smart antibodies that only work in the tumour microenvironment|
|Immune checkpoint inhibitors, such as anti-CTLA4 antibodies, have been demonstrated a thrilling efficacy in controlling many cancers. However, immune-related adverse events also occur to patients receiving treatment, which could be severe and harbour unwanted consequences. Part of the reason for these adverse events is anti-CTLA4 antibody-induced tissue resident Treg depletion, as Treg also expresses CTLA4. Pai and colleagues developed an engineered anti-CTLA4 antibody (referred to as anti-CTLA4 DVD) equipped with an outer domain that can be cleaved by an enzyme in the tumour microenvironment to unfold the inner CTLA4-binding domain, allowing the antibody only works in the tumour. The team published their results in the Journal of Clinical Investigation (here).
In order to mimic the clinical immune-related toxicities, the authors developed an animal model using Rag1-/- mice receiving wildtype naïve CD4+ T cells. Reconstructed mice treated with anti-CTLA4 antibodies presented diarrhoea and bodyweight loss, mimicking clinical observations. Histological damages and lymphocyte infiltration in the colon, liver, and lungs were evident in mice treated with anti-CTLA4 antibodies. Compared to anti-CTLA4 antibodies, anti-CTLA4 DVD had increased specificity and retention in the tumour, reduced immune-related toxicity, and comparable efficacy in tumour killing, by preserving tissue-resident Tregs (including a colitis model using adoptive T cell transfer) while remaining activities in the tumour microenvironment.
This study shed light on the application of the antibody that can be activated only in the tumour microenvironment to eliminate peripheral immune-related adverse effects.