Isatuximab
Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody medication for the treatment of multiple myeloma.
The most common side effects include neutropenia, infusion reactions, pneumonia, upper respiratory tract infection, diarrhoea and bronchitis.
Isatuximab is an anti-CD38 mAb intended to treat relapsed or refractory multiple myeloma. It entered in Phase II trials for multiple myeloma and T-cell leukemia in 2015.
Medical uses
In the United States it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. It is also indicated in combination with carfilzomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. As of September 2024, it is also approved in combination with lenalidomide, bortezomib and dexamethasone for newly diagnosed patients ineligible for a hematopoietic stem cell transplantation.In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy.
History
It was granted orphan drug designation for multiple myeloma by the European Medicines Agency in April 2014, and by the U.S. Food and Drug Administration in December 2016.Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma. The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.
Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.
A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with a completion date of 2021.
Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant. The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines. There is currently no treatment for MM, however promising improvements have been made and the study is still ongoing.
In March 2020, it was approved for medical use in the United States.
The U.S. Food and Drug Administration approved isatuximab-irfc in March 2020, based on evidence from a clinical trial of 307 subjects with previously treated multiple myeloma. The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.
The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma. Subjects were randomly assigned to receive either isatuximab-irfc or active comparator. Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Both subjects and health care providers knew which treatment was given. The trial measured the time patients lived without the cancer growing.
It was approved for medical use in the European Union in May 2020.
Structure and reactivity
The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking. Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.Reactions
Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly. Isatuximab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab. The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species.
Available forms
Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL solution in single-dose vial or 500 mg/25 mL solution in single-dose vial.Mechanism of action
Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment. CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells. This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cell-mediated cytotoxicity. Isatuximab-irfc is able to stimulate natural killer cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells. Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope. According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model.
In preclinical studies of B-cell malignancies, isatuximab demonstrated greater pro-apoptotic activity than daratumumab. It more effectively disrupted B-cell receptor signaling and inhibited the enzymatic activity of CD38. Structural analyses showed that isatuximab binding induced conformational changes in CD38 that impaired its enzymatic function, resulting in metabolic reprogramming and cell death. These findings support potential therapeutic applications for isatuximab beyond multiple myeloma, particularly in CD38-expressing B-cell malignancies.