Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab^®)

Abstract

The trifunctional antibody (trAb) catumaxomab is characterized by a unique ability to bind three different cell types: tumor cells; T-cells; and accessory cells. It binds to epithelial cell adhesion molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and to type I, IIa, and III Fcγ receptors (FcγRs) on accessory cells (e.g. natural killer cells, dendritic cells, and macrophages). Catumaxomab exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent, cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Catumaxomab represents a self-supporting system, as no additional immune cell activation is required for tumor eradication. The efficacy and safety of catumaxomab have been demonstrated in a pivotal phase II/III study in malignant ascites (MA) and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions of 10, 20, 50, and 150 µg on days 0, 3, 7, and 10, respectively. Catumaxomab was approved for the i.p. treatment of MA in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible in the European Union in April 2009. It is the first trAb and the first drug in the world approved specifically for the treatment of MA. Catumaxomab was awarded the Galen of Pergamon Prize, which recognizes pharmacological research for developing new and innovative drugs and diagnostics, in the specialist care category in 2010. The use of catumaxomab in other indications and additional routes of administration are currently being investigated to further exploit its therapeutic potential in EpCAM-positive carcinomas.

Design of in silico Trifunctional Antibody (hIgG1-FC: mouse-antiHER2× human-B7.1) Gene Cassettes and Expression Vectors: The Stage Prior to Production

“…The second signal is induced by the interactions of co-stimulatory protein, especially B7 proteins (CD80 and CD86), on the APC with their complementarity receptors, CD28, on the surface of the T cells. The B7 family consists of some Ig-like molecules, including B7.1 and B7.2 [12]. The obtained sequences were searched using BLAST.…”

“…Recent advances which bind to tumor cells and T-cells, and act via T-cell-mediated lysis. The BsAbs drugs, Catumaxumab and Ertumaxumab, have been approved by Food and Drug Administration (FDA) [11,12]. This study presented the researchers' effort in designing the in silico expression model of BsAbs which recognizes both HER2 and CD28, and utilizes NK cells.…”

“…Tri-functional monoclonal antibodies (Triomab) belong to the first generation of bispecific antibodies (bsAbs) targeting two different epitopes [6,7], such as ertumaxomab which, in turn, targets tumoral HER2/Neu antigen (by antiHER2 domains), T-cell CD3 receptor epitopes (by anti-CD3 domains), and accessory cells such as natural killer cells (NK cells), contributing to destroy cells, (by antibody Fc) through antibody-dependent as well as complementdependent induction of cytotoxicity (ADCC and CDCC, respectively) [8][9][10]. Completing the phase I and II of clinical trials related to ertumaxomab and catumaxomab (Triomabs) [11,12] and the effective low dose range (microgram dose range versus milligram dose, i.e., high dose administration) in cancer therapy [7,10,13,14] have triggered the incentive of designing in silico specific expression vectors for the production of this class of antibodies. As functional diversity for mAb and triomab gets equal to 4/6 (x₁/n₁) and 6/6 (x₂/n₂), respectively, p gets equal to 10/12 (x₁+x₂)/(n₁+n₂) resulting z and |z| scores to get equal to -1.55 and 1.55, respectively, which is less than z scores equal to 1.96 (α=0.05) and 2.576 (α=0.01).…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…92 PDGF receptors constitute promising targets for anticancer therapies as they are involved in the proliferation and survival of different tumors as well as in the regulation of the as immunostimulatory agents by taking T cells in the close proximity of tumor cells. 28,109,110 Another interesting approach that is being tested in phase I-II trials is known as pre-targeted radioimmunotherapy and is exemplified by TF2, a bispecific mAb that simultaneously targets the tumor-associated carcinoembryonic antigen (CEA) and a heterologous hapten peptide (IMP-288). 111 limited to) the so-called BiTEs (bispecific T-cell engagers).…”

“…Moreover, mAbs have already been successfully employed in vivo (in animal models of disease or patients) to: (i) neutralize circulating factors, (ii) activate immune effector mechanisms against Most mAbs that are currently approved for use in humans (irrespective of their indication) or under clinical evaluation belong to the IgG isotype. 2,4 There are at least six classes of mAbs that are relevant for cancer therapy: (i) mAbs that directly inhibit tumor cellautonomous pro-survival cascades (e.g., cetuximab and panitumumab, which inhibit the epidermal growth factor receptor, EGFR, and are currently approved for the treatment of colorectal cancer); 21 (ii) mAbs that interfere with the tumor-stroma interaction, thereby indirectly inhibiting tumor growth (e.g., bevacizumab, which blocks the vascular endothelial growth factor, VEGF, and is currently employed in the for the therapy of colorectal, breast, renal and lung cancer); [22][23][24] (iii) mAbs that bind to antigens expressed on the surface of tumor cells and function by selectively engaging immune effector mechanisms such as ADCC, 4,5 ADCP, 25 and CDC 6,7 (e.g., rituximab, a naked anti-CD20 in use for the therapy of lymphoma); 26,27 (iv) trifunctional (bispecific) mAbs, which can bind two different antigens while remaining capable of engaging immune effector functions (e.g., catumaxomab, an anti-CD3, anti-EpCAM chimeric mAb currently approved for the treatment of malignant ascites in patient with EpCAM + neoplasms); 28 (v) immunoconjugates (e.g., 90 Y-ibritumomab tiuxetan and 131 I-tositumomab, radionuclide-coupled anti-CD20 mAbs that are used for the therapy of lymphoma); 29,30 and (vi) immunostimulatory mAbs, i.e., mAbs that facilitate the development of a tumor-specific immune response by targeting the cancer cell/immune system crosstalk and the signaling pathways that this crosstalk elicits. An interesting sub-group encompassing these latter two categories is represented by immunoconjugates between putative tumor antigens and mAbs that target receptors expressed on the surface of dendritic cells (DCs), including CLEC9A, DC-SIGN, DEC205.…”