Abstract
Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody–drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.
Highlights
Fresh specimens from acute myeloid leukemia (AML) and multiple myeloma (MM) patients and normal peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from nondiseased donors were acquired from AllCells (Emeryville, CA, USA)
A 3.5-fold reduction in Antibody–drug conjugates represent a promising new class of anticancer therapeutics that combine the specificity of an antibody with the potent activity of cytotoxic drugs
Many of the antibody–drug conjugates (ADCs) that are in clinical development are based on antigens that had previously been tested as targets for traditional unarmed antibody therapeutics
Summary
The development of antibody–drug conjugates (ADCs) has become an effective approach for the treatment of cancer.[1,2,3,4] The ability to combine the specificity of an antibody directed to a cell surface antigen with the cytotoxicity of potent small molecular weight drugs, such as tubulin inhibitors and DNA cross-linking agents, has been demonstrated to confer an improved therapeutic index compared with more traditional chemotherapeutic agents.[1,2,3,4] The regulatory approvals of brentuximab vedotin and ado-trastuzumab emtansine have demonstrated that ADCs can provide significant clinical advantages compared with unconjugated antibodies.[4,5,6] There are currently more than 35 ADCs in clinical development,[7,8] and even though some promising results have been reported, the available data suggest that developing highly efficacious therapeutics through this modality may be more complex than initially expected.[9]One of the main challenges in the development of novel ADCs is the identification of a cell surface protein that is selectively expressed in tumors and that allows for efficient internalization of the payload to provide a clinical benefit.[10]. Another challenge is to couple a highly specific monoclonal antibody (mAb) to the appropriate linker–toxin combination to achieve the desired safety and efficacy profile.[11]
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