Leukemia is ideally suited to treatment with MAb because of the accessibility of malignant cells in the blood, spleen and lymph nodes. Moreover, the well-defined immunophenotypes of the various lineages and stages of hematopoietic differentiation have permitted the identification of antigenic targets. Recent studies in acute myeloid leukemia (AML) have focused primarily on CD33, a cell-surface glycoprotein found on most myeloid leukemias as well as committed myelomonocytic progenitor cells, but not on mature granulocytes or non-hematopoietic tissues. With years of experience in antibody discovery and bio-conjugation, BOC Sciences offers an extensive range of ADCs preparation services targeting the CD33. Highly potent toxins and toxin derivatives targeting a variety of cellular pathways are also available according to our clients’ specific demands.
CD33 is a member of sialic acid-binding immunoglobulin-type lectin (Siglec) family of immunomodulatory receptors. CD33 is expressed as a glycosylated 67 kDa type 1 transmembrane protein on monocytes, granulocytes, mast cells and myeloid progenitors. It is also found on macrophages, dendritic cells and can be displayed on subsets of B cells, activated T cells and natural killer cells. It is generally considered that CD33 is not expressed outside the hematopoietic system, although one study has shown CD33 to be expressed by microglial cells in the brain. Notably, CD33 is expressed on the cell surface of more than 80% of leukemia isolates from patients with AML with a very high average antigen density. The differential expression of CD33 on the surface of malignant AML blasts, but not on the surface of normal hematopoietic stem cells (HSCs), thus makes CD33 an ideal target for immunotherapy. Several immunotherapies targeting CD33, including antibody-drug conjugates, CAR-T cells and bispecific antibodies, are currently being evaluated in the clinic or are in preclinical development.
Fig. 1. Acute myeloid leukemia (AML).
The first ADC to receive FDA approval in 2000, for the treatment of AML, was gemtuzumab ozogamicin (Mylotarg®), consisting in a calicheamicin derivative bound to a humanized IgG4 mAb that targets the myeloid antigen CD33. After ten years of clinical use, Mylotarg® was withdrawn from the market in 2010, due to a potentially fatal hepatotoxicity, occurring in the form of veno-occlusive disease. Such condition was shown to derive from the obstruction of small blood vessels in the liver, caused by the ADC binding to its target, CD33, also expressed on the surface of healthy sinusoidal endothelial cells. Thereafter, Mylotarg®, in combination with daunorubicin and cytarabine, obtained a new marketing authorization at a lower and fractionated dose to improve treatment safety and prevent the rapid re-expression of CD33 on leukemia cells.
Fig. 2. Domain structure of CD33-related sialic-acid-binding immunoglobulin like lectins in human (Immunology vol. 2011, 132(1): 18-26).
Besides being recognized by Mylotarg®, CD33 is also targeted by other ADCs that reached clinical evaluation in recent years, such as IMGN779 and SGN-CD33A. IMGN779 utilizes the humanized anti-CD33 mAb Z4681A joined, through a cleavable disulfide linker, to a DNA-alkylating payload, DGN462, consisting of an indolinobenzodiazepine dimer with a monoimine moiety. Also in SGN-CD33A an anti-CD33 antibody, with engineered cysteine residues, is conjugated to DNA cross-linking synthetic pyrrolobenzodiazepine dimers (PBDs) via a highly stable, cathepsine B cleavable, maleimidocaproyl-valinealanine (MC-VC) dipeptide linker. This ADC has been tested in phase 1 clinical trials for CD33-positive AML as monotherapy or in combination with hypomethylating agents (azacitidine or decitabine).
CD33-Targeted Therapy in Acute Myeloid Leukemia (AML)
AML is a genetically heterogenous disease characterized by clonal expansion of leukemia cells. AML develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a heterogeneous disease clinically, morphologically, and genetically, and biological differences between adult and childhood AML have been identified. Statistics show that AML comprises 15-20% of all children less than fifteen years diagnosed with acute leukaemia. Relapse occurs in up to 40% of children with AML and is the commonest cause of death. The cell surface marker CD33 is an attractive therapeutic target in AML due to the frequent expression of this transmembrane glycoprotein on adult and childhood AML blasts and importantly identified on adult leukaemic stem cells (LSCs). Studies have indicated that approximately 90% of patients have myeloid blast cells expressing the CD33 surface antigen and since CD33 is reported to be absent from haematopoietic stem cells, it provides a selective AML target.
As a novel targeted therapeutic agent presenting significant potential and promising in the AML therapy, ADCs have obtained attractive attention. BOC Sciences is a service provider in the field of antibody-related drug development. We offer comprehensive ADCs development services for the targeted CD33 treatment. Our unique antibody screening and leading bioconjugate technology can help clients obtain optimal ADC candidates. Notably, BOC Sciences also offers comprehensive ADC development services for AML, which includes antibody screening, linker-cytotoxin synthesis, antibody-drug conjugation, and in vitro efficacy tests. With unique expertise in both chemical synthesis and biochemistry, we are confident in offering one-stop ADC development services to meet your special needs.