Clinical Experience with CD3 X CD19 Bispecific Antibodies in Patients with B Cell Malignancies

Abstract

In extensive preclinical testing, a CD3 x CD19 bispecific antibody (BsAb) induced killing of malignant B cells by resting T cells even in an autologous situation. In a 14 day clonogenic assay using a CD19+ pre-B cell line (REH), BsAb required repeated administration together with IL-2 to achieve a 5 log kill by resting peripheral blood T cells. Intravenously administered BsAb in an intrapatient dose escalation study of 3 patients with B cell non-Hodgkin's lymphoma showed limited toxicity (WHO grade II fever and chills) due to tumor necrosis factor-alpha (TNF-alpha) release by T cells. Pharmacokinetics with 2.5 mg BsAb showed peak levels of 200-300 micrograms/ml and a t1/2 of 10.5 h. The next patient, with chronic lymphocytic leukemia (CLL), received 0.6 mg BsAb/m2 as an i.v. infusion preceded by 1 MU IL-2/m2 s.c. Improved T cell activation was noted, as indicated by an increase in IFN-gamma, IL-6, IL-8, and IL-10, in addition to high TNF-alpha increases. TNF-alpha increases were highest on the first day. Toxicity remained restricted to grade II fever and chills, observed every day after the infusion of BsAb. No clear clinical effects were seen in this chemotherapy-resistant CLL patient with a high tumor burden. If subsequent patients also show limited toxicity, treatment of patients with a lower tumor load seems to be warranted to evaluate the efficacy of CD3 x CD19 BsAb therapy.

Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti‐CD20 × anti‐CD3), mediates efficient killing of B‐cell lymphoma cells even with very low CD20 expression levels

“…Bispecific antibodies directed against B-cell-specific antigens such as CD19 or CD20 have been under intensive investigation for the last 10-15 years, but limited clinical data showing only moderate responses 11,33,34 are available thus far. Moreover, the complicated and inefficient manufacturing process makes it difficult to produce sufficient amounts of antibody for clinical use.…”

Anti-CD3 × Anti-Epidermal Growth Factor Receptor (EGFR) Bispecific Antibody Redirects T-Cell Cytolytic Activity to EGFR-Positive Cancers In vitro and in an Animal Model

“…Most of these studies, however, are based on the strategy of injecting BiAbs alone into patients, which holds an increased risk for inducing dose-limiting toxicities associated with massive cytokine release (i.e., ''cytokine storm''; refs. 30,43). In contrast, we arm ex vivo expanded, autologous ATC with BiAbs, such as anti-CD3 Â anti-Her2 (Her2Bi) or anti-CD3 Â anti-CD20 (CD20Bi), before reinfusing them back into the patient.…”

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

“…Many strategies using bsAb for tumor therapy have designed reagents that recognize a TAA with one arm (such as c-erbB-2, 32 GD2, 33 or CD19 34 ) and the triggering molecules of immune effector cells with the other arm. [32][33][34] Because most TAAs that are targeted are also expressed on some normal cells, unwanted side effects may occur, particularly when the bsAb reagents are applied systemically.…”

“…[32][33][34] Because most TAAs that are targeted are also expressed on some normal cells, unwanted side effects may occur, particularly when the bsAb reagents are applied systemically. 35,36 There are several advantages to the decision to bind a bsAb first to a tumor vaccine for local application and to the choice of the foreign viral HN molecule, which is easily introduced ex vivo into human tumor cells, as a tumor target: (a) the HN is not expressed on any normal cells of the cancer patient, (b) targeting the bsAb to HN does not interfere with the tumors' TAA expression and presentation, and (c) a common anchoring molecule avoids the need to produce bsAb separately for every type of cancer.…”