Bispecific Monoclonal Antibodies for Intravenous Treatment of Carcinoma Patients: Immunobiologic Aspects

Abstract

Immunobiologic parameters measured during a phase I trial of intravenously (i.v.) administered bispecific monoclonal antibodies (BsmAb) in renal cell carcinoma (RCC) patients are described. The BsmAb used, BIS-1, is reactive with a pancarcinoma-associated 38 kDa transmembrane glycoprotein, EGP-2, as well with the CD3 complex. Patients received during a 2 h i.v. infusion F(ab')2 fragments of BIS-1 at doses of 1, 3, or 5 micrograms/kg body weight during concomitantly applied subcutaneous (s.c.) IL-2 treatment. Acute but transient BIS-1 F(ab')2-related toxicity was observed at the 3 and 5 micrograms/kg dose level, and the maximum tolerated dose (MTD) was set at 5 micrograms/kg. A dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes was found. The in vivo occupancy of CD3 molecules on T lymphocytes was highest at teh end of the infusion period and then rapidly decreased, as shown by flow cytometry. A much slower decrease of BIS-1 F(ab')2 binding was observed in vitro, suggesting migration of BIS-1 F(ab')2-loaded T lymphocytes from the circulation. A strong but transitory leukopenia was observed, in which LFA-1 alpha bright, CD3/CD8 double positive T cells left the circulation preferentially. This phenomenon was most likely induced by elevated TNF-alpha and IFN-gamma plasma levels, which were at a maximum shortly after the end of the infusion. Isolated peripheral blood mononuclear cells obtained from patients directly after treatment with BIS-1 F(ab')2 at the 3 and 5 micrograms/kg dose level showed increased EGP-2-directed antitumor activity.

Transient lymphocyte decrease due to adhesion and migration following catumaxomab (anti-EpCAM x anti-CD3) treatment in vivo

“…Administration of an EpCAM/CD3-bispecifi c BITE antibody to mice resulted in a transient increase in serum levels of TNF and IFN [17]. Another bispecifi c anti-CD3 antibody also caused a rapid increase in plasma levels of TNF and IFN in carcinoma patients [18,19].…”

“…A further study also showed that administration of a monospecific anti-CD3 antibody to patients after renal transplantation resulted in decreases in lymphocyte counts [20]. Administration of the bispecifi c antibody BIS-1 (anti-CD3 x anti-EGP-2) to renal cell carcinoma patients caused a rapid decrease in circulating mononuclear cells in the peripheral blood [18,19]. The effect was dose-dependent and there was a preferential decrease in LFA-1+CD3+/CD8+ lymphocytes [18].…”

Biodistribution Studies of Epithelial Cell Adhesion Molecule (EpCAM)-Directed Monoclonal Antibodies in the EpCAM-Transgenic Mouse Tumor Model

“…The accessibility of an Ag in organs can be influenced by differences in vasculature between organs or by differences in FcRn affinity of the mAb, which results in differences in transcellular transport subsequently leading to either more or less Ab being available for the target Ag (25,29). The Ag density per organ or the presence of the basal lamina, which has been suggested to shield the epithelial cells from the circulation in humans (3,30), can influence the tissue localization of the mAb as well.…”

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

“…[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. The specificity controls revealed that the bsAb did not bind to nonvirusmodified tumor cells and that the parental mAbs could not increase vaccine immunogenicity.…”