Graphical Abstract Highlights d Anti-4-1BB IgG2a depletes intratumoral Treg cells; IgG1 promotes CD8 T cell function d The efficacy of anti-4-1BB mIgG1 and anti-4-1BB mIgG2a depends on different FcgRs d Optimal tumor therapy requires sequential anti-4-1BB IgG2a and IgG1 or PD-1 blockade d Hinge-engineered anti-4-1BB mIgG2a/h2B mAb harnesses both mechanisms of action

Glyco-engineering has been developed to enhance the pharmacological properties of monoclonal antibodies (mAbs) resulting in superior immune effector function. Mogamulizumab is the first approved glyco-engineered therapeutic antibody and first approved mAb to target the CC chemokine receptor 4 (CCR4). CCR4 is principally expressed on Tregs and helper T cells (Th) where it functions to induce homing of these leukocytes to sites of inflammation. Tregs play an essential role in maintaining immune balance; however, in malignancy, Tregs impair host antitumor immunity and provide a favorable environment for tumors to grow. CCR4 is highly expressed by aggressive peripheral T-cell lymphomas (PTCLs), particularly adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Mogamulizumab is a humanized anti-CCR4 mAb with a defucosylated Fc region that enhances antibody-dependent cellular cytotoxicity (ADCC). In addition, mogamulizumab depletes CCR4(+) Tregs, potentially evoking antitumor immune responses by autologous effector cells. This ability is highly pertinent as subsets of malignant T cells are believed to function as CD4(+) Tregs, overexpressing CCR4. Clinical trials with mogamulizumab have demonstrated clinical efficacy and tolerability for the treatment of relapsed/refractory aggressive T-cell lymphomas, previously associated with very poor outcomes.

Immunomodulatory monoclonal antibody (mAb) therapy is at the forefront of developing cancer therapeutics with numerous targeted agents proving highly effective in selective patients at stimulating protective host immunity, capable of eradicating established tumours and leading to long-term disease-free states. The cell surface marker CD40 is expressed on a range of immune cells and transformed cells in malignant states whose signalling plays a critical role in modulating adaptive immune responses. Anti-CD40 mAb therapy acts via multiple mechanisms to stimulate anti-tumour immunity across a broad range of lymphoid and solid malignancies. A wealth of preclinical research in this field has led to the successful development of multiple anti-CD40 mAb agents that have shown promise in early-phase clinical trials. Significant progress has been made to enhance the engagement of antibodies with immune effectors through their interactions with Fcγ receptors (FcγRs) by the process of Fc engineering. As more is understood about how to best optimise these agents, principally through the fine-tuning of mAb structure and choice of synergistic partnerships, our ability to generate robust, clinically beneficial anti-tumour activity will form the foundation for the next generation of cancer therapeutics.