Loncastuximab tesirine

Identification

Summary

Loncastuximab tesirine is an antibody-drug conjugate used for the treatment of relapsed and refractory B-cell lymphomas.

Brand Names
Zynlonta
Generic Name
Loncastuximab tesirine
DrugBank Accession Number
DB16222
Background

Relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL) are a therapeutic challenge for patients who have undergone prior systemic therapies with limited success.1 Prognosis is poor and more effective therapies are needed to treat relapsed/refractory cases and improve survival.2 On April 23 2021, the Food and Drug Administration granted accelerated approval for the antibody-drug conjugate, loncastuximab tesirine-lpyl, also known as Zynlonta. This therapy was developed by ADC Therapeutics and its accelerated approval for relapsed or refractory B-cell lymphoma is based on promising results from the LOTIS-2 clinical trial.6,7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
151000.0 Da
Sequences
Not Available
Synonyms
  • Loncastuximab tesirine
  • loncastuximab tesirine-lpyl
External IDs
  • ADCT 402
  • ADCT-402
  • ADCT402

Pharmacology

Indication

Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma who have undergone two or more prior lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The above indication is approved under accelerated FDA approval following the results of clinical studies. Continued approval is dependant upon the results of confirmatory clinical trials.5

Pharmacology
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Drug Discovery
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Loncastuximab tesirine exhibits antitumour activity against malignant B-cells, treating lymphomas.1,6 Higher exposure in Cycle 1 of therapy in clinical trials was associated with an increased incidence of Grade ≥2 adverse reactions, including liver function test abnormalities, skin and nail reactions, and liver function test abnormalities.6

Mechanism of action

Human CD19 antigen is a membrane glycoprotein in the immunoglobulin superfamily expressed in the various stages of B-cell development; it is detected in most malignancies of B-cell origin. Additionally, CD19 has rapid internalization kinetics and does not shed into the general circulation, rendering it a useful therapeutic target for antibody-drug conjugates (ADCs) in the treatment of B-cell malignancies.3

Loncastuximab tesirine is an antibody-drug conjugate designed to target human CD19. It is a humanized monoclonal antibody and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin by a protease enzyme cleavable valine-alanine linker.2 The monoclonal IgG1 kappa antibody component binds to CD19, a transmembrane protein located on B-cell surfaces. The small molecule component, SG3199, functions as a PBD dimer and alkylating agent. Following binding to CD19, loncastuximab tesirine becomes internalized into the cell and subsequently proteolytic cleavage releases the SG3199 component. SG3199 binds to the DNA minor groove, forming cytotoxic DNA interstrand crosslinks, leading to B-cell cell death.6

TargetActionsOrganism
UB-lymphocyte antigen CD19
binder
Humans
Absorption

Due to its intravenous route of administration, loncastuximab tesirine is readily absorbed into the circulation.6 Cmax during Cycle 1 of therapy was 2995 μg/L and 3155 μg/L in Cycle 2. AUC was 15,245 - 22,823 μg*day/L during pharmacokinetic studies.4

Volume of distribution

In clinical studies, the average loncastuximab tesirine-lpyl volume of distribution was 7.11 liters, with a range between 7.19-8.43 liters.6

Protein binding

Not Available

Metabolism

The monoclonal antibody portion of loncastuximab tesirine-lpyl is catabolized into small peptides. In vitro studies show that the small molecule cytotoxin portion, SG3199, is metabolized by CYP3A4/5.6

Route of elimination

The main excretion pathways of SG3199 have not been formally studied in humans. SG3199 is thought to be minimally excreted by the kidneys.6

Half-life

The half-life of loncastuximab tesirine-lpyl was 7.06-12.5 days at steady-state.4,6

Clearance

In pharmacokinetic studies, the mean clearance of loncastuximab tesirine-lpyl decreased with time from 0.499 L/day after a single dose to 0.275 L/day at steady-state.6 One pharmacokinetic study measured a clearance ranging from 0.5-0.64 L/day.4

Adverse Effects
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Toxicity

LD50 information for loncastuximab tesirine is not readily available in the literature. Toxicity is increased at higher doses, and may lead to discontinuation.4,6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Loncastuximab tesirine.
AfatinibThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Afatinib.
AmbrisentanThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Ambrisentan.
AmiodaroneThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Amiodarone.
ApalutamideThe serum concentration of Loncastuximab tesirine can be decreased when it is combined with Apalutamide.
ApixabanThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Apixaban.
Arsenic trioxideThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Arsenic trioxide.
AsunaprevirThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Asunaprevir.
AvanafilThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Avanafil.
AvatrombopagThe serum concentration of Loncastuximab tesirine can be increased when it is combined with Avatrombopag.
Interactions
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Food Interactions
No interactions found.

Products

Products
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International/Other Brands
Zynlonta
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZynlontaInjection, powder, lyophilized, for solution10 mg/2mLIntravenousADC Therapeutics America, Inc.2021-04-30Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
7K5O7P6QIU
CAS number
1879918-31-6

References

General References
  1. Jain N, Stock W, Zeidan A, Atallah E, McCloskey J, Heffner L, Tomlinson B, Bhatnagar B, Feingold J, Ungar D, Chao G, Zhang X, Qin Y, Havenith K, Kantarjian H, Wieduwilt MJ: Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. Blood Adv. 2020 Feb 11;4(3):449-457. doi: 10.1182/bloodadvances.2019000767. [Article]
  2. Hamadani M, Radford J, Carlo-Stella C, Caimi PF, Reid EG, O'Connor OA, Feingold J, Ardeshna KM, Townsend WM, Solh M, Heffner LT, Ungar D, Wang L, Boni JP, Havenith K, Qin YG, Kahl B: Final Results of a Phase 1 Study of Loncastuximab Tesirine in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Blood. 2020 Nov 19. pii: 474210. doi: 10.1182/blood.2020007512. [Article]
  3. Zammarchi F, Corbett S, Adams L, Tyrer PC, Kiakos K, Janghra N, Marafioti T, Britten CE, Havenith CEG, Chivers S, D'Hooge F, Williams DG, Tiberghien A, Howard PW, Hartley JA, van Berkel PH: ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018 Mar 8;131(10):1094-1105. doi: 10.1182/blood-2017-10-813493. Epub 2018 Jan 3. [Article]
  4. Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, Solh M, Heffner LT, Ungar D, He S, Boni J, Havenith K, O'Connor OA: A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Epub 2019 Nov 4. [Article]
  5. FDA Approved Drug Products: Zylonta (loncastuximab tesirine-lpyl) for intravenous injection [Link]
  6. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma [Link]
  7. Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2) [Link]
RxNav
2540964
Wikipedia
Loncastuximab_tesirine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentRefractory Diffuse Large B Cell Lymphoma / Relapsed, Diffuse Large B-cell Lymphoma1
2Active Not RecruitingTreatmentRecurrent Diffuse Large B-Cell Lymphoma / Refractory Diffuse Large B Cell Lymphoma1
2RecruitingTreatmentRefractory Follicular Lymphoma / Relapsed Follicular Lymphoma1
1CompletedTreatmentBurkitt's Lymphoma / Chronic Lymphocytic Leukaemia (CLL) / Diffuse Large B-Cell Lymphoma (DLBCL) / Follicular Lymphoma (FL) / Mantle Cell Lymphoma (MCL) / Marginal Zone Lymphoma (MZL) / Non-Hodgkin's Lymphoma (NHL) / Primary Mediastinal B-Cell Lymphoma / Waldenström's Macroglobulinemia (WM)1
1TerminatedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
1, 2RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL) / Mantle Cell Lymphoma (MCL)1
1, 2TerminatedTreatmentDiffuse Large B-Cell Lymphoma (DLBCL) / Follicular Lymphoma (FL) / Mantle Cell Lymphoma (MCL)1
Not AvailableNo Longer AvailableNot AvailableRelapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous10 mg/2mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Receptor signaling protein activity
Specific Function
Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.
Gene Name
CD19
Uniprot ID
P15391
Uniprot Name
B-lymphocyte antigen CD19
Molecular Weight
61127.985 Da
References
  1. FDA Approved Drug Products: Zylonta (loncastuximab tesirine-lpyl) for intravenous injection [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Curator comments
Data supported by in vitro studies only and is not clinically relevant, according to prescribing information.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Zylonta (loncastuximab tesirine-lpyl) for intravenous injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Data supported by in vitro studies only and is not clinically relevant, according to prescribing information.
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: Zylonta (loncastuximab tesirine-lpyl) for intravenous injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Zylonta (loncastuximab tesirine-lpyl) for intravenous injection [Link]

Drug created on December 15, 2020 18:16 / Updated on July 03, 2021 01:49