GLK-33, anti-CD33 antibody-drug conjugate

GLK-33 is an ADC consisting of humanized anti-CD33 antibody lintuzumab and eight MMAU auristatin payloads per antibody. The antibody binds to the CD33 receptor on the surface of leukemia cells, liberates the cytotoxic drug, and causes cell death and immunologic reaction against cancer.

Mechanism of action

GLK-33 has both payload- and antibody-effector mechanisms

  1. GLK-33 binds to cell surface CD33 and is internalized into the leukemia cell, leading to receptor blockade and internalization.
  2. GLK-33 is degraded in the lysosome and the payloads are liberated.
  3. The active cytotoxic auristatin payload binds to tubulin and causes inhibition of tubulin polymerization and programmed cell death (apotosis).
  4. The payload can pass through cell membranes and kill bystander leukemia cells.
  5. Immune cells can bind to the antibody part of GLK-33 on the cell surface with Fc receptors, causing antibody-dependent cell-mediated cytotoxicity (ADCC) and immunologic memory against leukemia cells.
ADC Mechanism
In-vivo efficacy

High potency against CD33-positive cells

GLK-33 has high anti-cancer efficacy. In preclinical leukemia models, GLK-33 was effective against AML at single doses down to 100 μg/kg. GLK-33 had 3-fold better efficacy than corresponding MMAE auristatin ADC against AML in xenografted mice. The hydrophilic linkers joining the antibody and drug have excellent systemic stability, leading to improved tolerability and safety. In preclinical rat toxicology, GLK-33 was better tolerated than either gemtuzumab ozogamicin (currently marketed AML ADC) or MMAE auristatin ADC. High efficacy and safety combine to produce an exceptionally wide therapeutic window for GLK-33.

Test results
Cytotoxic payload of GLK-33

MMAU, novel auristatin with improved therapeutic window

Auristatins are the most widely used payload class in ADCs. They are potent microtubule disrupting agents that preferentially target cancer cells and act synergistically with other cancer drugs including immunotherapeutics. Glykos’ novel auristatin MMAU is a glucuronide modification of the standard auristatin MMAE that is currently being used in the marketed ADCs Brentuximab Vedotin (Adcetris®), Enfortumab Vedotin (Padcev®), and Polatuzumab Vedotin (Polivy®). Glykos’ linker-payload technology widens the therapeutic window of MMAU ADCs compared to MMAE ADCs by improving ADC pharmacokinetics, stability, and efficacy.

Auristatin