4.4.2 Monoclonal Antibodies in Clinical Trials [28...
Most cases of MF and SS express the CD4 molecule highly and constitutively on the malignant lymphocytes, making it an attractive candidate for therapeutic targeting.CD4 is a coreceptor of the T-cell receptor (TCR), normally expressed on T cells (helper T cells [TH] and Tregs), macrophages,monocytes, and dendritic cells.Development of effective anti-CD4 therapy early on was hampered by the development of anti-chimeric antibodies.The anti-CD4 antibodies were well tolerated and demonstrated some clinical efficacy.
In 2016, a novel anti-CD4 fully human mAb called zanolimumab that reacts with CD4-positive T cells and tumor cells and to a lesser degree with monocytes and macrophages has been developed.Zanolimumab has been shown to induce a dose-dependent decrease in T-cell activation by interference with interaction between the CD4 antigen and the major histocompatibility complex class II molecule and by inhibiting signal transduction through the TCR.It has also been shown to delete CD4+ cells by Fc-mediated ADCC.
In 2 prospective, multicenter phase 2 clinical trials (Hx-CD4-007 and Hx-CD4-008) with patients with relapsed/refractory MF or SS, 47 patients (38 with MF and 9 with SS; 25 patients with early-stage and 22 with advanced-stage disease), were treated with 17 weekly infusions of zanolimumab.Doses ranged from 280 to 580 mg for patients with early-stage disease and from 280 to 980 mg for patients with advanced-stage disease with assessment of response by Composite Assessment of Index Lesion Disease Severity.The RR was dose dependent with the highest response of 56% noted in the high-dose group with a median response duration of 81 weeks.The most common treatment-related AEs included inflammatory skin reactions and infections of the skin and upper respiratory tract.The infections were thought to be related to profound and long-term depletion of CD4+ lymphocytes from the peripheral blood.A phase 3 clinical trial in CTCL was suspended by the company.At this moment, zanolimumab is being tested in other non-cutaneous lymphomas and is showing clinical activity.(https://www.daowen.com)
Mogamulizumab is the first approved glycoengineered therapeutic humanized IgG1 mAb and the first approved mAb to target the CC chemokinereceptor 4 (CCR4).It is has a defucosylated Fc region that leads to enhanced ADCC without a complement effect.CCR4 is principally expressed on Tregs and TH, including malignant CD4+ CTCL cells, where it functions to induce homing of these leukocytes to sites of inflammation.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 (ATLL) and CTCL.In addition to targeting malignant cells, mogamulizumab depletes CCR4+ Tregs, potentially evoking antitumor immune responses by autologous effector cells.This mode of action is especially important in CTCL, where the malignant cells were shown to have Treg phenotype and function.55 In addition, CCR4+ T cells are the main source of IL-31 in CTCL, an antibody associated with intractable pruritus.Neutralizing the IL-31 pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.
Mogamulizumab is approved for use in Japan, based on the phase 2 clinical trial demonstrating an overall RR of 35%, including 5 patients (14%) with a CR.The median PFS was 3.0 months.
In a phase 1/2 trial in the United States evaluating the efficacy of mogamulizumab in 41 pretreated patients with CTCL, no dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation period.In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression.The overall RR was 36.8%:47.1% in SS and 28.6% in MF.Of the19 (94.7%) patients with greater than or equal to B1 blood involvement, 18 had a response in blood, including 11 CRs.Adverse events were nausea (31.0%),chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); most events were grade 1/2.There were no significant hematologic effects.
Since the discovery of high expression of killer cell immunoglobulin-like receptor (KIR) 3DL2(KIR3DL2) on malignant SS cells, it has become an established marker for malignant cells in SS,but it has also been shown to be expressed in MF.59 Thus it may be a universal marker for CTCL.KIRs are transmembrane glycoproteins normally expressed by NK cells and a small subset of T cells, but they are highly and constitutively expressed in CTCL.
A recent study reported the development of IPH4102, a humanized mAb that targets the immune receptor KIR3DL2.Potent antitumor properties of IPH4102 were documented in allogeneic human CTCL cells and a mouse model of KIR3DL2(+) disease.IPH4102 antitumor activity was mediated by ADCC and phagocytosis.IPH4102 improved survival and reduced tumor growth in mice inoculated with KIR3DL2(+) tumors.Ex vivo IPH4102 selectively and efficiently killed primary Sézary cells.These results present a preclinical proof of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.