Proposed mechanism of action of KADCYLA

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KADCYLA structure

The first HER2-targeted antibody-drug conjugate with Herceptin® (trastuzumab)1,5

KADCYLA: a single agent with 3 components

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.1

DM1=derivative of maytansine; MCC=4-(N-maleimidomethyl) cyclohexane-1-carboxylate.

KADCYLA is designed to be stable in circulation, reducing systemic exposure and preserving activation until the antibody reaches the HER2+ cell11-13

As seen in preclinical studies, KADCYLA maintains the HER2 suppression and anticancer activities of trastuzumab while delivering cytotoxic DM1 to HER2-expressing cells1

Monoclonal antibody

  • Many normal cells express HER214
  • HER2-positive (HER2+) cancer cells can express up to 100 times more HER2 than normal cells
  • Many tumors that progress after prior HER2 therapy continue to express HER2 and demonstrate sensitivity to microtubule inhibitors (e.g. taxanes)1,12,15
  • Trastuzumab selectively binds to HER2 receptors1
    • Suppresses downstream signaling pathways to inhibit tumor cell proliferation and survival1,16
    • Triggers antibody-dependent cell-mediated cytotoxicity (ADCC)1
    • Inhibits HER2 shedding1

Linker1,12,13

  • MCC linker was designed to provide a more stable bond between trastuzumab and the active cytotoxic agent, with the goal of minimizing systemic exposure in circulation
  • Preserves the active cytotoxic agent until the antibody has reached the HER2+ cell

Cytotoxic agent

  • A microtubule inhibitory agent that induces cell cycle arrest and cell death
  • Potent cytotoxic drug that is designed to be inactive and nontoxic in its conjugated form, reducing systemic exposure12
  • Provides cytotoxicity previously unavailable for clinical use
    • DM1, a maytansinoid, is approximately 20 to 200 times more potent than taxanes and vinca alkaloids1,10
    • Once the target cell is destroyed, DM1 is unable to cross the membrane of other cells and is therefore not associated with a bystander killing effect12,13

Proposed mechanism of action of KADCYLA

Multiple antitumor activities from a single agent

Proposed mechanism of action for KADCYLA, based on preclinical models1,8,11

Dual antitumor activity with HER2 suppression and the release of DM1 inside HER2-targeted cells

HER2+ antitumor activities1,8,10

1. HER2 binding: Selectively binds to the HER2 receptor at subdomain IV.

2. HER2+ antitumor activities

  • Disrupts ligand-independent HER2 signaling (antiproliferative and apoptotic effects)
  • Mediates ADCC
  • Inhibits HER2 shedding

DM1* cytotoxic activity1

3. Internalization: once bound, the KADCYLA/HER2 receptor complex is internalized via endocytosis.
4. DM1 release: KADCYLA undergoes proteolytic degradation inside the target cell and releases the active chemotherapy, DM1.
5. DM1 cytotoxicity: DM1 binds to microtubules and inhibits their polymerization, causing cell-cycle arrest and cell death.

*Cytotoxic DM1-containing catabolites (primarily lysine-bound emtansine).1


KADCYLA for early breast cancer

KADCYLA for metastatic breast cancer

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