Improved Therapeutic Responses in a Xenograft Model of Human B Lymphoma (Namalwa) for Liposomal VincristineversusLiposomal Doxorubicin Targeted via Anti-CD19 IgG2a or Fab′ Fragments

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Abstract
Purpose: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates. Experimental Design: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[αCD19]) or its Fab′ fragments (SIL[Fab′]). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model. Results: SIL[αCD19] or SIL[Fab′] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab′] had longer circulation times than SIL[αCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab′] had better therapeutic outcomes than SIL[αCD19] for the drug DXR but were equally efficacious for the drug VCR. Conclusions: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab′] versus SIL[αCD19] led to superior therapeutics for DXR-loaded immunoliposomes.