ADCT-402 is an antibody-drug conjugate (ADC) directed towards a protein called CD19 (Target). It is composed of a humanized monoclonal antibody binding to CD19 conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. ADC Therapeutics has reported preclinical data demonstrating potent antitumor activity of ADCT-402 against CD19-expressing B-cell malignancies1.

The target: CD19

ADCT-402 targets CD19, a protein whose expression in healthy cells is restricted to pre-B cells, where it is involved in the signal transduction of B-cells and B-cell precursors2 (Figure 1).

Figure 1: Simple schematic of CD19

CD19 is an ideal target for an ADC approach as it is highly expressed in a wide range of B-cell hematological tumors, including certain forms of lymphomas and leukemias, while its expression in healthy tissues is restricted2. Indeed, CD19 expression has been demonstrated in many types of non-Hodgkin lymphoma (NHL)3 including Burkitt’s lymphoma, follicular lymphoma and diffuse large B-cell lymphoma as well as in newly diagnosed and relapsed pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), B-ALL and hairy cell leukemia (HCL)4. To read more about NHL and ALL, click here and here, respectively.

The toxin: PDB dimer

The toxin employed in ADCT-402 belongs to the latest generation of a novel class of highly potent PBD dimers5. PBD dimers work by binding in the minor groove of the DNA, where they induce highly cytotoxic cross-links that cause the cell to die. Importantly, PBD dimers are relatively non-distorting of the DNA structure, making them hidden to cellular repair mechanisms and, therefore, allowing the DNA cross-links to persist longer within the DNA which results in increased and prolonged activity against cancer cells6.

PBD dimers are very potent and are believed to have a different mode of action when compared to warheads like maytansinoids or auristatins6, which are commonly used in other ADCs such as trastuzumab emtansine and brentuximab vedotin, respectively (Figure 2).

Figure 2: Warheads potency for ADCs7

Proposed mechanism of action of ADCT-402

ADC Therapeutics has conducted preclinical work1 showing that following administration of ADCT-402, its CD19-specific antibody component targets ADCT-402 to the tumor (Step 1) and, upon binding of the antibody to CD19 on the tumor cell surface, ADCT-402 is internalized (Step 2), degraded (Step 3) and the PBD dimer toxin is released inside the cell (Step 4), where it binds in the minor groove of DNA and forms highly cytotoxic DNA interstrand cross-links (Step 5) that will ultimately kill the cancer cell (Step 6) (Figure 3).

Figure 3: Proposed mechanism of action of ADCT-402

References

  • Zammarchi, F., et al., Pre-clinical Development of ADCT-402, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate (ADC) Targeting CD19-Expressing B-cell Malignancies. Blood, 2015. 126(23).
  • Wang, K., et al., CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol, 2012. 1(1): p. 36.
  • Anderson, K.C., et al., Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood, 1984. 63(6): p. 1424-33.
  • Scheuermann, R.H. and E. Racila, CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma, 1995. 18(5-6): p. 385-97.
  • Tiberghien, A., et al., Design and synthesis of tesirine, a clinical antibody-drug conjugate pyrrolobenzodiazepine dimer payload. ACS Medicinal Chemistry Letter, 2016.
  • Hartley, J.A., The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin Investig Drugs, 2011. 20(6): p. 733-44.
  • https://www.spirogen.com/technology/overview.html