PR1 on the edge of humoral immunotherapy

The development of a monoclonal antibody against the PR1/HLA-A2 complex that is aberrantly expressed on myeloid malignancies gives the opportunity to better define the potential benefits and risks of targeting the tumor-associated proteinase 3 and neutrophil elastase-specific PR1 antigen by both cellular and humoral immunotherapeutic approaches.¹ 

Previously, Molldrem et al have identified PR1 as a potential target for cellular immunotherapy.^2,3  They and others^3,4  reported the presence of cytotoxic T lymphocytes (CTLs) directed against the PR1 epitope in patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), and demonstrated a correlation with disease outcome. Vaccination studies using synthetic PR1 peptides were able to show the development of biologically relevant immune responses to PR1 in some patients.^4,5  Unfortunately, sustained clinical responses were rare, and ex vivo clonal expansion of high avidity T cells from responding patients directly documenting in vivo expansion of T cells has not been reported.⁶  This may indicate that endogenous presentation of PR1 peptide in HLA-A2 molecules could have prevented the in vivo development of high avidity T cells by natural negative selection, thereby impairing successful vaccination strategies.⁷  However, Molldrem and colleagues have previously reported absence of recognition of normal cells by PR1-specific CTLs, suggesting that presentation of the antigen on normal cells may be absent.⁸  The complexity of studying detailed, tissue-specific expression and recognition of the PR1 epitope using T cells has complicated these analyses.

The development of an anti–PR1/HLA-2 complex-specific antibody by Sergeeva et al as reported in this issue of Blood has strongly facilitated the detailed characterization of the PR1/HLA-A2 complex as potential target for immunotherapy.¹  The authors have used an elegant approach to generate a monoclonal murine antibody directed against the human PR1/HLA complex, and demonstrated specific recognition of this T-cell epitope. Sergeeva and colleagues have used this antibody to specifically map the PR1/HLA-A2 epitope within the hematopoietic compartment.

Preferential recognition of AML (precuror) cells by both direct staining and cytotoxicity assays, including a complement-depended cytotoxicity, was demonstrated, indicating that PR1 may be a potentially relevant target antigen. However, clear, significant expression on normal hematopoietic stem cells, myeloblasts, and monocytes was also demonstrated, illustrating expression of the antigen under normal circumstances. This constitutive expression may explain the absence of high-avidity T cells under normal conditions, preventing a significant clinical immune responses after vaccination in most cases. The results demonstrate that there may be a limited therapeutic window to target PR1. Low-avidity antibodies or T cells may suppress AML or CML maturating cells without eliminating clonogenic leukemic stem cells, whereas high-avidity T cells and antibodies may successfully target the leukemic stem cells but at the cost of potent hematopoietic toxicity. Whether such temporary toxicity would still allow therapeutic applications of the PR1/HLA-A2–specific antibody needs to be determined. Antibodies and T cells make use of different effector mechanisms to kill target cells. Sergeeva et al have generated a great tool to further study not only the potential benefits and risks of using PR1 as a target for immunotherapy, but their findings also allow further elucidation and comparison of the mechanism of action of humoral and cellular immunotherapeutic strategies.