Multiple myeloma is an incurable hematologic malignancy formed by malignant or transformed plasma cells in which the cancerous plasma cells can crowd out healthy blood cells, impair bone strength and weaken the immune system.
And while this disease is a relatively uncommon cancer (in the United States, the lifetime risk of getting multiple myeloma is 1 in 143 or 0.7%), the American Cancer Society estimates that about 30,770 people will be diagnosed (16,400 in men and 14,370 in women) with multiple myeloma and about 12,770 patients will die (6,830 in men and 5,940 in women) as a results of the disease in the United States for 2018.
“[Although relatively uncommon,] multiple myeloma is the second most common blood cancer in the United States and remains an incurable disease despite recent medical advances,” noted Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.
Today, multiple myeloma is managed with sequential lines of treatment that typically yield shorter durations of disease control with each subsequent relapse, and some patients receive more than four lines of treatment over the course of their disease.
As a results, there exists a major unmet medical need for patients with multiple myeloma.
“[To effectively treat multiple myeloma and to increase the stringency and durability of remissions] patients are in need of new targeted treatment options,” Lechleider added.
Antibody-drug Conjugate
SGN-CD48A, a potent CD48-targeting antibody-drug conjugate or ADC, utilizing the potent microtubule disrupting cytotoxic agent monomethyl auristatin E (MMAE) and a PEGylated β-glucuronidase-cleavable linker system that can enable a higher drug-to-antibody ratio or DAR, is one of the potential therapies for the treatment of multiple myeloma.
The investigational drug includes a humanized anti-CD48 monoclonal antibody to which eight molecules of MMAE have been conjugated.
The proprietary linker technology developed by Seattle Genetics incorporates a PEG side chain and self-stabilizing maleimide designed to achieve homogenous DAR with decreased plasma clearance and increased preclinical antitumor activity. As a result, the investigational ADC has demonstrated to be highly stable in circulation and release an increased amount of MMAE upon internalization into CD48-expressing cells, producing greater antitumor activity in preclinical studies.
CD48
CD48, also known as SLAMF2 (Signaling Lymphocyte Activation Molecule family member 2), is a GPI-anchored membrane protein in the SLAM family of immunoreceptors expressed in 90% (90/100) of human multiple myeloma patient samples examined by flow cytometry.
It is also expressed on B and T lymphocytes, natural killer (NK) cells, and other immune cell types where it functions to modulate immune cell activation, proliferation, and differentiation.
Mode of action
Following binding of CD48 at the myeloma cell surface, SGN-CD48A internalizes and traffics to lysosomal vesicles. This is followed by intracellular MMAE drug released from SGN-CD48A in myeloma cells induced cell cycle arrest at G2/M phase, phospho-histone H3 (Ser-10) phosphorylation, and caspase 3/7 dependent apoptotic cell death.
In preclinical development SGN-CD48A has demonstrated potent cytotoxic activity (EC50 values 1.0 – 11 ng/mL) against a panel of human multiple myeloma cell lines, with CD48 expression levels of 135,000 – 480,000 receptors per cell. However, the drug had negligible cytotoxic activity against normal resting human B, NK, and T lymphocytes.
Phase I trial
As part of the development SGN-CD48A, a first patient was dosed in a phase I clinical trial evaluating the safety and tolerability of the investigational agent.
“SGN-CD48A uses our latest ADC technology, and the initiation of this phase I trial in relapsed or refractory multiple myeloma highlights our continued leadership in ADCs as we address this challenging disease,” Seattle Genetics’ Lechleider added.
The phase I study is a multicenter open-label dose-escalation trial designed to enroll approximately 75 patients with relapsed or refractory multiple myeloma.
Schedule
In this phase I clinical trial SGN-CD48A will be administered at an initial dosing interval of every three weeks. The primary objectives of the trial are to evaluate the safety and tolerability of SGN-CD48A and to identify the maximum tolerated dose (MTD). Key secondary objectives include assessing the antitumor activity and identifying the recommended single-agent dose and schedule.
