Biologic response to anti-CD16 monoclonal antibody therapy in a human immunodeficiency virus-related immune thrombocytopenic purpura patient

Abstract

A patient with refractory human immunodeficiency virus (HIV)-related immune thrombocytopenic purpura (ITP) was treated with 3G8 (anti-CD16) monoclonal antibody on days 1, 3, and 8 (25, 25, and 50 mg were administered intravenously, respectively). Side effects were those expected after the administration of a xenogenic protein, but a severe bone pain occurred from the second injection. At the time of the initiation of the treatment the platelet count was 20,000/mm3 and the absolute CD4 number was 100/mm3. We obtained a long-term correction of thrombocytopenia and, to a lesser extent, there was a stabilization of CD4 lymphocytes for 18 months. We observed a significant stimulation of natural killer (NK) function and an elevation in the serum level of tumor necrosis factor alpha, interferon gamma, and granulocyte- macrophage colony-stimulating factor. This suggests that in HIV-related ITP the removal of platelets is mediated by low-affinity Fc gamma receptors (CD16). The stimulation of NK function and elevation in CD4+ lymphocytes may be related to the production of cytokines by activated human NK cells through the interaction of their CD16-bearing receptor with the 3G8 monoclonal antibody. This observation warrants confirmation and further clinical trials.

HPA‐1a‐mediated platelet interaction with monocytes in vitro: involvement of Fcγ receptor (FcγR) classes and inhibition by humanised monoclonal anti‐FcγRI H22

“…Previous work from our laboratory has demonstrated that neonatal Mo express adult levels of FccRI and FccRII (10) and show normal attachment and ingestion of IgG anti-Rh(D)-coated red cells (35). Earlier studies have suggested the involvement of FccRIIIa in immune platelet clearance in vivo (15,16). Hence, anti-HPA-1a-sensitised platelets might preferentially interact with the circulating FccRIII-positive Mo subpopulation (36,37) which is reduced in cord blood (38).…”

“…(14). Moreover, anti-FccRIII mAb 3G8 decreased the elimination of immune complexes on administration to chimpanzees (14) and was moderately bene®cial in the treatment of patients with chronic ITP (15,16). More recently the role of the human FccRIIa in the immune clearance of platelets was demonstrated in a transgenic mouse model (17).…”

Monoclonal antibody 197 (anti‐FcγRI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down‐modulation of FcγRI on circulating monocytes

“…Clarkson et al (1986) also demonstrated that RBCs opsonized with IgG had an increased clearance time after treatment of the patient with anti-FcRIII mAb, suggesting that platelet destruction may be due, at least in part, to low affinity Fc receptors. Soubrane et al (1993) used the same anti-FcRIII mAb 3G8 to treat a patient with refractory human immunodeficiency (HIV)-related ITP, and the patient subsequently had long-term correction of the thrombocytopenia. Some of the toxicity described with the use of the mAb 3G8 (Clarkson et al, 1986;Soubrane et al, 1993) may have been due to the fact that 3G8 could have bound to the soluble form of FcRIII, resulting in immune complex formation.…”

“…Soubrane et al (1993) used the same anti-FcRIII mAb 3G8 to treat a patient with refractory human immunodeficiency (HIV)-related ITP, and the patient subsequently had long-term correction of the thrombocytopenia. Some of the toxicity described with the use of the mAb 3G8 (Clarkson et al, 1986;Soubrane et al, 1993) may have been due to the fact that 3G8 could have bound to the soluble form of FcRIII, resulting in immune complex formation. A soluble form of FcRI (CD64) has not been described, and immune complex formation should therefore not be a complication with the use of anti-FcRI antibody.…”

“…The relative importance of each of these receptors in removing IgG-coated platelets is not yet clear. The mAb 3G8 (anti-FcRIII) has been shown to decrease the clearance of immune complexes in an animal model (Clarkson et al, 1986), and has been administered to cITP patients with some positive results (Clarkson et al, 1986;Soubrane et al, 1993). The rise in the platelet count observed after anti-CD16 mAb infusion could have been due to specific blockade of the FcRIII, or also, in part, have been the result of an aspecific blockade of the MPS by overloading the system with IgG-coated neutrophils.…”