Antibodies Target Underlying Immune Triggers of Multiple Myeloma
Chicago, IL—Several forms of antibodies are in clinical use or in development for the treatment of multiple myeloma. Ivan M. Borrello, MD, Director, Cell Therapy and cGMP Biologics Core, Johns Hopkins Kimmel Cancer Center, Baltimore, provided an overview of the current landscape at ASCO 2017.
The 4 categories of antibodies he discussed in the context of multiple myeloma were naked antibodies, antibody drug conjugates, bispecific antibodies, and Y-traps.
Naked antibodies include elotuzumab (Empliciti) and daratumumab (Darzalex). Elotuzumab is an anti-SLAMF7 monoclonal antibody that targets the CS1 glycoprotein. In lenalidomide (Revlimid)-naïve patients with multiple myeloma, the combination of elotuzumab, lenalidomide, and dexamethasone showed a significant improvement in progression-free survival (PFS) versus lenalidomide and dexamethasone at 1 and 2 years, which led to the FDA’s approval of elotuzumab in 2016.
“Interestingly, this antibody has virtually no measurable activity in the absence of an immunomodulatory drug [IMiD]; it’s only in the combination with lenalidomide and potentially other IMiDs that this begins to show clinical activity,” said Dr Borrello. “It does appear to have activity in high-risk disease, as manifest by responses in [patients with] 17p-negative, t(4;14), and 1q-positive amplification.” Studies are currently ongoing in the nonrelapsed setting.
In a randomized phase 3 clinical trial of daratumumab conducted in patients with relapsed or refractory multiple myeloma, the overall response rate was improved from 63% to 83% by adding daratumumab to bortezomib and dexamethasone, with an associated improvement in PFS. The greatest benefit with daratumumab occurred in patients who had received 1 previous line of therapy, indicating that earlier treatment may provide the most benefit for patients with relapsed or refractory disease.
In another phase 3 clinical trial, daratumumab added to lenalidomide and dexamethasone increased the overall response rate to 93% compared with 76% with lenalidomide plus dexamethasone alone, with a rate of complete response or better of 43% versus 19%, respectively. A 63% reduction in the risk for disease progression or death was seen with the addition of daratumumab. In patients who achieved complete remission, a higher percentage who received the triplet agents achieved minimal residual disease negative compared with patients who received the doublet.
Antibody Drug Conjugates
Antibody drug conjugates incorporate an antibody linked to a cytotoxic agent. “This is a way of releasing chemotherapy in a very targeted manner,” said Dr Borrello. An antibody that is being actively tested is one targeting B-cell maturation antigen (BCMA), which is expressed on malignant plasma cells. Preclinical studies demonstrate selective and potent activity. Early clinical data show significant clinical responses, with an objective response rate of 66.7%, with some ongoing complete remissions, when using a dose of ≥3.4 mg/kg. The main toxicity appears to be ocular toxicity (with most cases presenting after the first cycle) that can be controlled with ocular steroids. Transient thrombocytopenia was also experienced.
Bispecific Antibody Constructs
Bispecific antibody constructs (bispecific T-cell engager) bind to T-cells and tumor cells, directing the cytolytic activity of T-cells selectively to tumor cells. One such construct is the recently approved drug blinatumomab (Blincyto), which binds CD19 and CD3. Bispecific antibody formats are immunoglobulin (Ig)G-like molecules and non–IgG-like molecules. The non–IgG-like molecules lack an Fc domain, a complication of which is a short half-life necessitating continuous infusion, “but the benefit of that is a strong tissue penetration.” In contrast, IgG-like molecules have an Fc domain and a longer half-life, obviating the need for long infusions, but tissue penetration is weaker.
EM801 is a BCMA antibody currently being explored. Another target is FcRH5; an antibody directed against it is still in the preclinical stage.
A Y-trap is a bifunctional immunostimulatory antibody-ligand trap that can “soak up” immunosuppressive molecules to enhance the activity of an antibody, said Dr Borrello. The extracellular domain of the Y-traps designed for cancer thus far have been TGF-beta, PD-1, or RANK. An interleukin-6-TGF-beta Y-trap was shown to have a potent antitumor effect in myeloma versus a single antibody given alone.