CD48 as a novel molecular target for antibody therapy in multiple myeloma

Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.     

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia

Background

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.

Design and Methods

Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.

Results

Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6–65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.

Conclusions

Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.     

Nodo-paranodopathy: Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies

In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain–Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region.     

Daclizumab: humanized monoclonal antibody to the interleukin-2 receptor

Daclizumab is a humanized antibody that binds to the α-chain of the interleukin-2 receptor and blocks the action of interleukin-2. It is approved for the prevention of organ allograft rejection using five 1 mg/kg doses every second week, starting at the time of transplant. Since approval, activity has primarily focused on the efficacy of shorter courses, typically two doses, and its use in steroid or calcineurin inhibitor elimination immunosuppressive protocols. In small trials, it appears that two doses are safe, effective and allow sparing of other toxic drugs. Outside the field of transplantation, the drug has been tested in a variety of autoimmune diseases including uveitis, diabetes, multiple sclerosis, ulcerative colitis and various dermatologic diseases. A new subcutaneous formulation is being developed to facilitate chronic dosing in these autoimmune diseases.     

Current status of monoclonal antibody therapy for the treatment of inflammatory bowel disease

Crohn’s disease and ulcerative colitis are complex diseases that have required the use of multiple modalities to aid in treatment. With an increasing understanding of the underlying pathogenetic mechanisms and identification of specific therapeutic targets, monoclonal antibody treatment has been an ideal strategy for inducing and maintaining remission in these patients. This article addresses approved agents and the supporting data justifying their use in Crohn’s disease and ulcerative colitis, the safety of and immunologic reactions to these agents, as well as newer agents for treatment.     

An update on treatment strategies for common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunological disease with variable severity, ranging from mild forms of infections to chronic progressive complications. The hallmark of this disorder is hypogammaglobulinemia due to an unknown molecular defect in immune regulation. The primary clinical manifestations are recurrent infections that may lead to structural damage of affected organs. Adequate intravenous immunoglobulin (Ig) therapy has dramatically changed the prognosis of this disorder, and the advent of home subcutaneous Ig therapy has further improved the quality of life of these patients. Aberrant T-cell functions predispose to autoimmune, inflammatory and lymphoproliferative complications, as well as malignancies in a variable percentage of CVID patients. Immunosuppressive anti-inflammatory therapies and chemotherapy are used, although always in conjunction with adequate replacement Ig therapy and adjunct antimicrobial prophylaxis. Any organ can be involved and therefore a multidisciplinary approach to the management of this disorder is essential.     

The evolution of allergen and non-specific immunotherapy: past achievements,current applications and future outlook

Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook.     

Risk factors for renal disease in systemic lupus erythematosus and their clinical implications

Lupus nephritis is one of the most common severe manifestations of systemic lupus erythematosus and is associated with significant morbidity and mortality. Genetic, ethnic and hormonal factors may influence the presence and severity of renal involvement and therefore affect the outcome and overall prognosis of patients. In this review, we will discuss the association of known lupus risk factors in developing renal disease and explore the recent literature to identify potential risk factors and their clinical implications in terms of diagnostic vigilance, management and prognosis.     

Complement deficiency and systemic lupus erythematosus: consensus and dilemma

The involvement of the complement system in the pathogenesis of autoimmune diseases is a matter of debate. However, the link between complement abnormalities and systemic lupus erythematosus (SLE) is well established and widely described. Homozygous and/or heterozygous complement-component deficiencies of the classical pathway (C1q, C1r, C1s, C4A, C4B and C2) are causally associated with susceptibility to the development of SLE. Although the severity of the disease and the strength of the association are heterogeneous for deficiencies of these proteins, they commonly cause peculiar SLE syndromes with an early age of onset, a susceptibility to bacterial infections and negative anti-dsDNA antibodies. In this review, we highlight the available data on complement deficiency and SLE with a focus on deficiencies in classical complement pathway components. We also discuss the paradox of the link between complement deficiency and lupus. The complement system acts as a ‘friend’ through the clearance of immune complexes and apoptotic cells, which explains the close association between complement deficiency and lupus. It also acts as an ‘enemy’ by participating in the effector inflammatory phase of the autoimmune response. Understanding the importance of complement deficiencies should provide novel targets for therapeutic interventions in the modulation of the immune response.     

Hashimoto’s thyroiditis: TGAb,TPOAb, TRAb and recovery from hypothyroidism

Hashimoto described four patients with goiter. The histology of the goiter was characterized by diffuse lymphocytic infiltration, fibrosis and epithelial cell destruction. Thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) have been used to diagnose Hashimoto’s thyroiditis. Patients with positive TGAb and/or TPOAb have been assumed to have Hashimoto’s thyroiditis. Approximately 10% of those with positive TGAb and/or TPOAb have hypothyroidism. There are two types of autoimmune thyroiditis: goitrous Hashimoto’s thyroiditis and atrophic thyroiditis. The latter patients have blocking antibody (thyroid-stimulating hormone [TSH]-stimulation blocking antibody [TSBAb]). TSBAb is a TSH-receptor antibody (TRAb). TSBAb causes thyroid atrophy and hypothyroidism. TGAb and/or TPOAb do not necessarily cause hypothyroidism. Hypothyroid patients with Hashimoto’s thyroiditis usually receive life-long l-thyroxine therapy. However, spontaneous recovery from hypothyroidism has been reported. Patients who had Hashimoto’s hypothyroidism and then Graves’ hyperthyroidism (and vice versa), have also been reported. Hashimoto’s hypothyroidism and Graves’ hyperthyroidism could be the opposite spectrums of one disease.