Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells.

B-cell maturation antigen (BCMA) expression has been proposed as a marker for the identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Consistent BCMA expression was confirmed on MM biopsies (29/29 BCMA+), and it was further demonstrated that BCMA is expressed in a substantial number of lymphoma samples, as well as primary chronic lymphocytic leukemia B cells.

The complement receptor 2/factor H fusion protein TT30 protects paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and C3 fragment.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis because of the lack from erythrocyte surface of the complement regulators CD55 and CD59, with subsequent uncontrolled continuous spontaneous activation of the complement alternative pathway (CAP), and at times of the complement classic pathway. Here we investigate in an in vitro model the effect on PNH erythrocytes of a novel therapeutic strategy for membrane-targeted delivery of a CAP inhibitor. TT30 is a 65 kDa recombinant human fusion protein consisting of the iC3b/C3d-binding region of complement receptor 2 (CR2) and the inhibitory domain of the CAP regulator factor H (fH).

Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases.

To selectively modulate human complement alternative pathway (CAP) activity implicated in a wide range of acute and chronic inflammatory conditions and to provide local cell surface and tissue-based inhibition of complement-induced damage, we developed TT30, a novel therapeutic fusion protein linking the human complement receptor type 2 (CR2/CD21) C3 fragment (C3frag = iC3b, C3dg, C3d)-binding domain with the CAP inhibitory domain of human factor H (fH). TT30 efficiently blocks ex vivo CAP-dependent C3frag accumulation on activated surfaces, membrane attack complex (MAC) formation and hemolysis of RBCs in a CR2-dependent manner, and with a ∼ 150-fold potency gain over fH, without interference of C3 activation or MAC formation through the classic and lectin pathways. TT30 protects RBCs from hemolysis and remains bound and detectable for at least 24 hours.

First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers.

Background: ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes.

Methods And Results: This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.