Proposed mechanism of action of KADCYLA

KADCYLA structure

The first HER2-targeted antibody-drug conjugate

*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.

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 HER29
    • HER2-positive (HER2+) cancer cells can express up to 100 times more HER2 than normal cells
  • Trastuzumab selectively binds to HER2 receptors1
    • Suppresses downstream signaling pathways to inhibit tumor cell proliferation and survival1,10
    • Triggers antibody-dependent cell-mediated cytotoxicity (ADCC)1
    • Inhibits HER2 shedding1

Linker

  • MCC linker stabilizes KADCYLA in circulation to release DM1 after entering the target cell1,4

Cytotoxic agent

  • A microtubule inhibitory agent that induces cell cycle arrest and cell death
  • Provides cytotoxicity previously unavailable for clinical use
    • DM1, a maytansinoid, is approximately 20 to 200 times more potent than taxanes and vinca alkaloids1,8

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

  • Suppresses ligand-independent HER2 downstream signaling (antiproliferative and apoptotic effects)
  • Triggers the antibody-dependent cell-mediated cytotoxicity (ADCC) immune response
  • Inhibits HER2 shedding

DM1* cytotoxic activity1

3. Internalization: once bound, the KADCYLA/HER2 receptor complex is internalized via endocytosis.
4. DM1 release: KADCYLA is degraded inside the tumor to release 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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