ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer–Containing Antibody–Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies

Abstract

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.

Recent developments in immunotherapy of acute myeloid leukemia

“…Results of randomized phase III trials are eagerly awaited in order to estimate the risk-benefit ratio between a potential increase in response rates and the discussed side effects due to on-target off-leukemia toxicities and toxin-induced hepatic toxicity. In order to increase target cell specificity of the therapy, alternative target antigens are being evaluated in preclinical (i.e., CLL-1, SAIL) [39–41] and early clinical studies (i.e., CD25, FLT3) [42, 43]. …”

The emerging role of anti‐CD25 directed therapies as both immune modulators and targeted agents in cancer

“…ADCT-301 is composed of the human IgG1 HuMax â -TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead (Fig 3) (Flynn et al, 2016). ADCT-301 is composed of the human IgG1 HuMax â -TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead (Fig 3) (Flynn et al, 2016).…”

“…ADCT-301 is composed of the human IgG1 HuMax â -TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead (Fig 3) (Flynn et al, 2016). In vivo, a single dose of ADCT-301 resulted in dose-dependent and targeted antitumour activity against both subcutaneous and disseminated CD25-positive lymphoma models (Flynn et al, 2016). Although effects on IL2 signalling have been demonstrated for anti-CD25 antibodies, HuMax-TAC did not demonstrate direct cytotoxicity in vitro.…”

“…ADCT-301 is the first ADC that targets CD25. ADCT-301 is composed of the human IgG1 HuMax â -TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead (Fig 3) (Flynn et al, 2016). This drug demonstrated highly potent and selective cytotoxicity against a panel of CD25expressing human lymphoma cell lines.…”

Passive Monoclonal and Polyclonal Antibody Therapies

“…In addition, there are clinical phase I studies against multiple solid tumors to be completed in 2021. 232,233 Agents abandoned or not found to be beneficial include apolizumab, denintuzumab mafodotin (HBU-12), iratumumab (MDX060), and lucatumumab (HCD122). 212,234,235 Anaplastic large cell lymphoma Brentuximab vedotin (Adcentrix) is an FDA-approved medication for patients with refractory or relapsed anaplastic large cell lymphoma who achieved CR.…”