Zynlonta, the first new ADC drug targeting CD19, has been approved!

On April 23, 2021, the FDA approved the antibody-conjugate drug Loncastuximab tesirine (Zynlonta) for the treatment of diffuse large B-cell lymphoma, which is still in the treatment of non-Hodgkin’s lymphoma, mantle cell lymphoma and follicular lymphoma Phase I clinical trial stage.

The drug was originally developed by ADC Therapeutics.
In 2013, MedImmune obtained the collaborative research and development authorization of Loncastuximab tesirine.

In June 2017, the FDA granted Loncastuximab tesirine the orphan drug designation for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.

Zynlonta Mechanism of Action Antibody-Drug Conjugates (ADC): A monoclonal antibody drug targeting a specific antigen and a small molecule cytotoxic drug conjugated through a linker, except for the traditional small molecule chemotherapy The powerful killing effect also has the tumor targeting of antibody drugs.

Picture A shows the general structure of ADC, including humanized/human monoclonal antibody (mAb), cleavable/non-cleavable chemical linker, and a small molecule cytotoxin load.

Antibodies and cytotoxic drugs are coupled via linkers.

Picture B shows the mechanism of action of ADC drugs.
ADC drugs combine with target cell surface antigen receptors to form a complex (1), enter the cell through endocytosis (2), and the complex is transported to the lysosome for processing (3) , Cytotoxic molecules are released into the cells (4), the toxin molecules bind to the target (5), and induce cell death (6).Loncastuximab tesirine-lpyl is an ADC drug that targets CD19.
The monoclonal IgG1 kappa antibody component binds to human CD19 (transmembrane protein expressed on the surface of cells of the B lineage).
The small molecule component is SG3199, a PBD (pyrrolobenzodiazepine).
Miscellaneous, can recognize and bind to specific DNA sequences) dimers and alkylating agents (with cytotoxic effects).

SG3249 is also called tesirine.

The molecular weight of Loncastuximab tesirine-lpyl is approximately 151 kDa.

An average of 2.
3 SG3249 molecules are attached to each antibody molecule.
The antibody molecule is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

After binding to CD19, the next step in the internalization of Loncastuximab tesirine-lpyl is the release of SG3199 small molecules through protein cleavage.
The released SG3199 binds to the DNA minor grooves and forms highly cytotoxic DNA inter-strand cross-links, thereby Disrupt the necessary DNA metabolism processes such as replication, and induce cell death.

CD19 is a popular target for the treatment of B-cell malignant tumors.
In animal models of lymphoma, Loncastuximab tesirine-lpyl also shows certain anti-cancer activity.

 Zynlonta Research and Development In March 2016, the open-label, adaptive dose escalation, multi-center clinical trial (NCT02669264) for the treatment of acute lymphoblastic leukemia began.

In March 2016, a clinical phase I dose escalation trial (NCT02669017) was conducted in patients with relapsed or refractory B-cell lineage non-Hodgkin's lymphoma (B-NHL).

In August 2018, the second phase of the open-label single-arm therapy clinical trial (NCT03589469) was started for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

In December 2018, an open-label phase I clinical trial (NCT03685344) was started for patients with advanced diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma.

In December 2018, an open-label clinical Phase I/II trial (NCT03684694) began for patients with advanced diffuse large B-cell lymphoma or mantle cell lymphoma.

LOTIS-2 clinical trial: LOTIS-2 (NCT03589469) is an open-label single-arm clinical trial for 145 relapsed patients or diffuse large B-cell lymphoma that is still difficult to control after at least 2 previous systemic treatments (DLBCL) Adult patients, the trial excluded patients with large masses and active central nervous system lymphoma.

The FDA's approval of Zynlonta is based on the key result data of the second phase of the LOTIS-2 trial that began in 2018.

In June 2020, Therapeutics SA announced mature data from LOTIS 2 at the 25th European Society of Hematology (EHA) virtual conference.

Patients received 0.
15 mg/kg of Zynlonta every 3 weeks for 2 cycles, and then received 0.
075 mg/kg of Zynlonta every 3 weeks for the following cycles, and received treatment until the disease progressed or unacceptable toxicity appeared.

Among the 145 patients enrolled, the median age was 66 years (range 23 to 94), 59% were male, and 94% of patients had ECOG (an index used to evaluate general health and tolerance to treatment, 0-5 , 0 points means that the activity ability is completely normal) The performance status is 0 to 1.

97% of patients reported race, of which 90% were white, 3% were black, and 2% were Asian.

The proportion of unspecified DLBCL diagnosed is 88% (including 20% ​​of DLBCL caused by low-grade lymphoma), and the proportion of high-grade B-cell lymphoma is 8%.

The median of previous treatments was 3 (range 2 to 7), refractory disease was 63%, previous stem cell transplantation was 17%, and previous chimeric antigen receptor (CAR) T cell therapy was 9%.

The results showed that the overall remission rate of Zynlonta reached 48.
3%, the complete remission rate reached 24.
1%, and the partial remission rate reached 24.
1%.

Among the 70 patients who got remission, the median time to remission was 10.
3 months.

Summary ADC drugs have emerged in an endless stream in recent years.

The selection of antibodies, linkers, small molecule toxins, and the design of coupling methods continue to promote the optimization of ADC drugs, which not only expands the therapeutic window, but also creates differentiated competition between ADC drugs.

Among the ADC drugs on the market before, there are 8 targeted targets, namely CD33, CD30, CD22, CD79β, HER2, Nectin-4, Trop-2, BCMA, and Zynlonta is the first ADC drug targeting CD19.
As ADC Therapeutics CEO Chris Martin said: “The FDA approval of Zynlonta is an exciting advancement for patients with r/r DLBCL and a transformational event for ADC Therapeutics.

” I believe that with the upsurge of ADC research and development, Aiming at the discovery of targets for various types of tumors such as hematomas and solid tumors, ADC drugs can be further developed and are expected to become a new generation of broad-spectrum anticancer drugs.

If there are any mistakes, please correct me.

If the picture is infringing, please contact to delete the reference: 1, https://adctherapeutics.
com/our-products/2, Tsuchikama K, An Z.
Antibody-drug conjugates: recent advances in conjugation and linker chemistries.
Protein Cell.
2018 Jan;9(1):33-46.
doi: 10.
1007/s13238-016-0323-0.
Epub 2016 Oct 14.
PMID: 27743348; PMCID: PMC5777969.
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