The Preclinical and Clinical Evaluation of VB6-845: An Immunotoxin with a De-Immunized Payload for the Systemic Treatment of Solid Tumors

Abstract

One of the challenges in cancer therapy is to eradicate tumor cells while minimizing the toxic side effects to normal tissue that can rapidly become dose-limiting. In this regard, the unique specificity of antibodies enables the targeting of antigens that are differentially or aberrantly expressed on tumor cells while ignoring their normal counterparts [1]. To date, six IgG antibodies have received FDA approval for the treatment of cancer, Herceptin (Trastuzumab), Rituxan (Rituximab), Avastin (Bevacizumab), Campath (Alemtuzumab), Erbitux (Cetuximab), and Vectibix (Panitumumab), and all have shown varying degrees of clinical and commercial success [2]. While designed to target tumor cells with nanomolar affinity, clinical evidence would suggest that the anticancer mechanisms mediated by these antibodies are not on their own sufficient to provide a prolonged clinical benefit [3].To that end, other strategies have been explored to enhance antibody potency while still exploiting their targeting function. One such approach has been to attach a cytotoxic payload to an antibody that when delivered to a cancer cell induces a highly potent cell death signal [4]. The most common payloads attached to antibodies or antibody fragments are small molecule drugs, radionucleotides, and toxins [1, 5–8]. Two radionucleotide-conjugated antibodies Zevalin (Ibritumomab tiuxetan) and Bexxar (Tositumomab-/I131) and one antibiotic-conjugated antibody Mylotarg (Gemtuzumab Ozogamicin) have been approved, although Mylotarg was subsequently withdrawn [9]. In addition, Ontak a diptheria toxin (DT) conjugated to an IL2 cytokine received approval for the treatment of cutaneous T cell lymphoma [10]. A variety of antibody–drug conjugates (ADCs) such as the anti-HER2 trastuzumab-DM-1 are currently being evaluated in the clinic as antibody conjugates have proven themselves superior to the naked antibody in xenograft tumor model [11]. Similarly, a variety of immunotoxins have been evaluated in the clinic, but as yet none have received FDA approval; however, those targeting leukemic cancers such as BL22, an anti-CD22 dsFv linked to truncated Pseudomonas exotoxin A (ETA), have been particularly successful [12, 13].