Loncastuximab tesirine

Loncastuximab tesirine or ADCT-402 is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19, which is expressed in a wide range of B cell hematological tumors.[1] The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL).

Loncastuximab tesirine
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetCD19
Clinical data
Other namesADCT-402
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6544H10048N1718O2064S52
Molar mass147481.45 g·mol−1

Technology

The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors[2] including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.[3]

Clinical trials

Two phase I trials are evaluating the drug in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia.[4] At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented.[5] Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).[6][7]

Orphan drug designation

Loncastuximab tesirine was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.[8]

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References
  1. WHO Drug Information: International Nonproprietary Names for Pharmaceutical Substances
  2. Wang K, Wei G, Liu D (November 2012). "CD19: a biomarker for B cell development, lymphoma diagnosis and therapy". Experimental Hematology & Oncology. 1 (1): 36. doi:10.1186/2162-3619-1-36. PMC 3520838. PMID 23210908.
  3. "Pyrrolobenzodiazepine". ADC Review.
  4. Clinical trial number NCT02669017 for "ADCT-402 in B-NHL" at ClinicalTrials.gov
  5. Kahl B, Hamadani M, Caimi PF, Reid EG, Havenith K, He S, Feingold JM, O'Connor O (June 2017). "First clinical results of ADCT‐402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B‐cell linage NHL" (PDF). Hematol Oncol. 35 (S2): 49–51.
  6. "First clinical results of ADCT-402". ADC Review.
  7. Bainbridge K. "Grandfather fighting deadly cancer reveals scans of tumors after testing new drug". Mirror.
  8. "ADCT-402 Orphan Drug Designation" (PDF). ADC Therapeutics press release.
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