Mogamulizumab and the Treatment of Ccr4-Positive T-Cell Lymphomas

Abstract

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.

A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19+tumor cells

“…[3][4][5] Nevertheless, the demand for even more efficacious treatments catalyzed the development of a new class of bispecific immune cell-recruiting antibodies. Such antibodies specifically, with extreme potency, recruit particular immune effector cells, and are able to recruit NK cells, 30 T cells, 23 …”

“…The principal optimizations pursued are enhancement of effector function and selection of tumor-targeting cellular marker. The Fc-optimization strategy relies upon engineering the Fc-domain to achieve more potent interaction with the Fcg receptors expressed on endogenous immune effector cells; Fc-optimized antibodies, targeting CD20, obinutuzumab, 3 and targeting CCR4, mogamulizumab, 4 have been approved, and another targeting CD19, MOR208, 5 has entered clinical trials.…”

Tumor microenvironment as a target of malignant gliomas treatment

“…Было показано, что системная бло-када CCL2 существенно снижала степень моноцитарно-ма-крофагальной инфильтрации опухоли, а в комбинации с темозоломидом значительно увеличивала выживаемость подопытных животных [8]. Могамулизумаб, моноклональ-ное антитело к CCR4 (рецептору к CCL2 и ССL22), одобрен к применению при рефрактерных Т-клеточных лимфомах/ лейкозах [9]. Продолжается его изучение при других опухо-лях [10].…”

Novel immunotherapy for adult T-cell leukemia/lymphoma: Targeting aurora kinase A

“…1 Although a recently introduced therapeutic agent, mogamulizumab, a monoclonal antibody for anti-C-C chemokine receptor 4 (CCR4), is expected to improve the survival of ATL patients, 2 in daily practice, ATL still remains refractory to conventional chemo-radiotherapies, producing a poor prognosis. 3 On the other hand, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been favored as a viable option for effective treatment of ATL.…”

“…5 Since CCR4 is also expressed by normal Treg cells, mogamulizumab might also have the benefit of depleting the immunosuppressive effect by Treg cells. 2 In addition, immune checkpoint inhibitors, ipilimumab (anti-CTLA-4) and pembrolizumab (anti-PD-1) are demonstrating great promise for the treatment of refractory malignancies. Taken together, these antibodies, by limiting immunosuppressive factors, might be beneficially combined with AURKA-directed immunotherapies, offering considerable promise of improved outcomes for patients with refractory ATL.…”