ABSTRACT
The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.
Subject(s)
Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Immunomodulation/drug effects , Neoplasms/immunology , Neoplasms/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 9/antagonists & inhibitors , Animals , Gene Expression , Humans , Immunoglobulin G/pharmacology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Mice, Knockout , Neoplasms/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolismABSTRACT
BACKGROUND: Long-term results after obstetric anal sphincter injury (OASI) are poor. We aimed to improve the long-term outcome after OASI by lessening symptoms of anal incontinence. METHODS: In a prospective study at Malmö University Hospital, twenty-six women with at least grade 3B OASI were classified and sutured in a systematic way, including separate suturing of the internal and external sphincter muscles with monofilament absorbable sutures. The principal outcome assessed by answers given to six questions, was a difference in anal incontinence score, between the study group and two control groups (women with prior OASI [n = 180] and primiparous women delivered vaginally without a diagnose of OASI [n = 100]). RESULTS: An anal incontinence score of zero (i.e., no symptoms) was found in 74% of the study group, 47% of the OASI control group, and 66% of the vaginal control group (p = 0.02 and 0.5, as compared to the study group). CONCLUSIONS: A modified suturing technique was followed by significant improved one-year symptoms of anal incontinence as compared to historical cases.