ADCT-301 is an antibody-drug conjugate (ADC) directed towards a protein called CD25 (Target). It is composed of a monoclonal antibody specific for CD25 (HuMax®-TAC, licensed from Genmab A/S), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. ADC Therapeutics has reported preclinical data demonstrating potent antitumor activity of ADCT-301 against CD25-expressing haematological tumors1.

The target: CD25

ADCT-301 targets CD25, a molecule expressed mainly on activated T-cells, where it forms part of the IL-2 receptor complex, which is important for conveying immunological and growth signals from the outside into the cell (Figure 1).

Figure 1: Simple schematic of CD25

CD25 is an attractive target for an ADC approach as it is expressed in a wide range of hematological malignancies, including certain forms of lymphomas and leukemias, while its expression in healthy organs is restricted2.

In lymphoma, CD25 expression has been demonstrated in Hodgkin’s lymphoma3 (HL) and many types of non-Hodgkin’s lymphoma (NHL) including follicular lymphoma4 and diffuse large B-cell lymphoma5. To read more about HL and NHL, click here and here, respectively.

In leukemia, CD25 expression has been demonstrated in newly diagnosed and relapsed acute myelogenous leukemia (AML)6, in late-stage myelodysplastic syndrome related AML and in Philadelphia-positive acute lymphoblastic leukemia or acute lymphoid leukemia (ALL)7. Interestingly, CD25 expression correlates with poor prognosis in AML and ALL8,9. To read more about AML and ALL, click here and here, respectively.

The toxin: PDB dimer

The toxin employed in ADCT-301 belongs to the latest generation of a novel class of highly potent PBD dimers10. 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 cross-links to persist longer within the DNA which results in increased and prolonged activity against cancer cells11.

PBD dimers are very potent and are believed to have a different mode of action when compared to warheads like maytansinoids or auristatins11, which are commonly used in other ADCs such as trastuzumab emtansine and brentuximab vedotin, respectively (Figure 2).

Figure 2: Warheads potency for ADCs12

Proposed mechanism of action of ADCT-301

ADC Therapeutics has conducted preclinical work1 showing that following administration of ADCT-301, its CD25-specific antibody component targets ADCT-301 to the tumour (Step 1) and, upon binding of the antibody to CD25 on the tumor cell surface, ADCT-301 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-301

References

  • Flynn MJ, et al., ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Molecular Cancer Therapeutics, 15(11);1-13, 2016.
  • Morris, J.C. and T.A. Waldmann, Advances in interleukin 2 receptor targeted treatment. Ann Rheum Dis, 2000. 59 Suppl 1: p. i109-14.
  • Schnell, R., et al.,  Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin's lymphoma. Leuk Lymphoma, 1998. 30(5-6): p. 525-57.
  • Fujiwara, S.I., et al., Clinical features of de novo CD25-positive follicular lymphoma. Leuk Lymphoma, 2013.
  • Fujiwara, S., et al., Clinical features of de novo CD25(+) diffuse large B-cell lymphoma. Hematology, 2013. 18(1): p. 14-9.
  • Gonen, M., et al., CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood, 2012. 120(11): p. 2297-306.
  • Geng, H., et al., Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discov, 2012. 2(11): p. 1004-23.
  • Miltiades, P., et al., Expression of CD25 antigen on CD34+ cells is an independent predictor of outcome in late-stage MDS patients treated with azacitidine. Blood Cancer J, 2014. 4: p. e187.
  • Nakase, K., et al., Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a poor prognosis. Leukemia, 2007. 21(2): p. 326-32.
  • 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