ADC Development Services Targeting CD33

Antibody-drug conjugates (ADCs) represent an innovative and promising therapeutic agent due to the advantages of the high specific anti-tumor activity. As a global service provider in the field of ADCs design and development, Creative Biolabs has world-class facilities and experienced team to offer integrated services targeting the CD33. Our end-to-end services include the production of specific antibody, the synthesis of high quality drug as well as effective conjugation development.

Introduction of CD33

CD33, also known as p67, SIGLEC3 or SIGLEC-3, is a transmembrane receptor glycoprotein. It belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family with endocytic properties. CD33 is mainly expressed on the normal multipotent myeloid precursors, unipotent colony-forming cells, maturing granulocytes and monocytes. It consists of an extracellular Ig-like domain at amino-terminal, a transmembrane domain, and a cytoplasmic tail. The intracellular tail of CD33 contains 2 conserved tyrosine-based inhibitory signaling motifs, which confers CD33 an important role in regulating the inflammatory and immune responses via inhibiting of tyrosine kinase-driven signaling pathways. Currently, CD33 is regarded as a target for the treatment of acute myeloid leukemia. It is also a useful marker in the diagnosis of the Alzheimer's disease.

Schematic structure of single-chain bispecific CD33/CD3 antibody and simplified proposed mode of action of drug-induced T-cell mediated cytolysis.Fig.1 Schematic structure of single-chain bispecific CD33/CD3 antibody and simplified proposed mode of action of drug-induced T-cell mediated cytolysis. (Laszlo, 2014)

Anti-CD33 ADC in Acute Myeloid Leukemia (AML)

CD33 is expressed on the malignant blasts in almost all patients with AML and is considered as the main target in the ADCs development for the AML therapy. Gemtuzumab ozogamicin represents the first generation ADC targeting the CD33, which is composed of an anti‑CD33 monoclonal antibody (mAb) conjugated to an enediyne DNA-binding antibiotic, calicheamicin through a cleavable hydrazone linker. It was approved by the FDA in 2000 for the AML therapy. Gemtuzumab ozogamicin displays the safe delivery of higher cumulative doses and substantially improves outcome in patients with AML, which is the front-line therapy for AML.

Schematic structure of Gemtuzumab ozogamicin. Fig.2 Schematic structure of Gemtuzumab ozogamicin. (Walter, 2012)

AVE9633 is the second generation ADC against the CD33, composed of the thiol-containing maytansine derivative (DM4) linked to a humanized IgG1 anti‑CD33 mAb (huMy9‑6) via a cleavable disulfide linker. AVE9633 has been investigated in clinical trial in patients with relapsed or refractory AML as a single agent.

The third-generation ADCs include Vadastuximab talirine (also known as SGN‑CD33A) and MGN779, which have been developed targeting the CD33. Vadastuximab talirine consists of the pyrrolobenzodiazepine (PBD) dimer and an anti-CD33 IgG1 antibody via a maleimidocaproyl valine-alanine dipeptide linker. PDB can cause the cell death by crosslinking DNA and blocking cell division. Vadastuximab talirine showed significant antitumor activity in a series of AML animal models. The Phase I trial results demonstrated that the ADC has promising complete response rate. Besides, a phase III trial of this ADC in combination with azacitidine or decitabine for older patients with newly diagnosed AML has been initiated.

IMGN779 is an ADC composed of an anti-CD33 mAb, the indolinobenzodiazepine DGN462 drug and an optimized cleavable disulfide linker. The ADC presents powerful antitumor activity, bystander killing and low systemic toxicity in preclinical and clinical trials. So far, IMGN779 has entered phase I trials.

What Can We Do for You?

Equipped with state-of-the-art research and manufacturing facilities, Creative Biolabs provides a comprehensive range of ADCs development services targeting the CD33 to help customers accelerate their drug development projects. We also provide custom services based on the requirements of the clients to meet the specific demand. Please contact us for more information.

Our ADCs services include but not limited to:

References

  1. Laszlo, G. S.; et al. The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood reviews. 2014, 28(4): 143-153.
  2. Walter, R. B.; et al. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012, 119(26): 6198-6208.

For lab research use only, not for any in vivo human use.


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ADC Development for Leukemia: Disease Research:
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