HUMANIZED IgG1 AND IgG4 ANTI-CD4 MONOCLONAL ANTIBODIES

Abstract

This study demonstrates that the in vivo effects of CDR-grafted OKT4A are dependent on its isotype. The depleting mAb CDR-OKT4A/hIgG1 significantly delays the entry of CD4+ cells into the graft, inhibiting the early phase of rejection. However, graft rejection occurs when CD4+ cells eventually infiltrate the graft, even in the presence of depressed levels of circulating CD4+ cells. Both isotypes demonstrated therapeutic efficacy: graft survival was prolonged over controls. In the case of CDR-OKT4A/hIgG4, neither lymphocyte depletion, antigenic modulation, nor prevention of infiltration is necessary for a beneficial effect, which indicates that this mAb blocks CD4 function or renders the CD4+ cell less responsive. The lack of depletion is a feature of potential clinical advantage in minimizing the risk of excessive immunosuppression.

CD4+ T Cells Contain Early Extrapulmonary Tuberculosis (TB) Dissemination and Rapid TB Progression and Sustain Multieffector Functions of CD8+ T and CD3− Lymphocytes: Mechanisms of CD4+ T Cell Immunity

“…To address this possibility, macaques were depleted of CD4+ T cells using the humanized mAb CDR-OKT4A–huIgG1 (40, 42, 43), administered i.v. 3 times at an interval of every two weeks at a dose of 50 mg/kg during the study, and evaluated for changes in early infection and progression statuses.…”

“…The CD4 depleting Ab is “CDR-OKT4A/hIgG1”. It is an Ab that combines the CDR (complementarity-determining region) of murine OKT4A(not OKT4) with the V framework and the constant regions of human k light chain and IgG1 heavy chain(40). OKT4A is different from OKT4 as OKT4A binds to an epitope on the CD4 molecule distinct from that recognized by OKT4, and these antibodies do not cross-block each other(40, 41).…”

“…The doses were calculated on macaque body weight every time, held in sterile plastic syringes and injected slowly over a period of at least 10 minutes. The administration of depleting Ab led to almost complete depletion of CD4+ T cells in vivo during Mtb infection(36, 40, 42, 43). …”

An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

“…However, autologous antibodies can be induced against a variety of fully human biological agents that are used for therapy (39)(40)(41)(42)(43)(44)(45)(46). Depending on their epitope specificity, autoreactive anti-CD4 antibodies have been shown to mediate CD4 ϩ T cell depletion, suppression of T cell-dependent immune responses, or various other forms of immune dysregulation (47)(48)(49)(50)(51)(52)(53)(54), effects that define safety concerns for HIV vaccine testing.…”

Induction of transplantation tolerance in non-human primate preclinical models

“…The importance of antibody isotype in determining the biologic function of humanized monoclonal antibodies targeting CD4 was emphasized in a later study (Mourad et al 1998). This study demonstrated that humanized antibodies based upon an IgG4 isotype coated but did not deplete CD4 positive T cells.…”