Title preparations containing 14.7% Sb(NAP), 14.5% Sb(TP15), and 12.2% Sb(TP2) had s.c. LD50 values in mice of 385, 350, and 600 mg./kg., resp., while the corresponding i.v. LD50 values were 435, 450, and 600 mg./kg., resp.Na antimony tartrate and K antimony tartrate had s.c. LD50 values of 48-55 mg./kg., and the latter had an i.v. LD50 of 65 mg./kg.The symptomatology induced by toxic doses of the chelates was identical to that of the unchelated Sb emetics.The antimonyl tartrates had an average single curative dose in mice infected with Trypanosoma equiperdum of 11 mg./kg., s.c., while TP15 and TP2 had an average single curative dose of 14 mg./kg., s.c.; the resp. min. clearing doses for the antimonyl tartrates for the TP15 and TP12 were 2.7 and 1.8 mg./kg., resp.T. venezuelense in mice appeared less sensitive to antimonials; the min. clearing dose for Na anti-monyltartrate and for NAP was approx. the same, 3.6-3.9 mg./kg., s.c., and no curative action was obtained by a single administration.The activity of the chelates against Schistosoma mansoni in mice was identical to that of the Sb tartrates; no difference was encountered between the Na and K salts.

HaematologicaQ1 · MEDICINE

Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy

Q1 · MEDICINE

Article

Author: Valerius, Thomas ; Peipp, Matthias ; Kellner, Christian ; Gramatzki, Martin ; Otte, Anna ; Cieker, Michael ; Krohn, Steffen ; Rösner, Thies ; Klausz, Katja ; Nimmerjahn, Falk ; Lux, Anja

Despite several therapeutic advances, patients with multiple myeloma (MM) require additional treatment options since no curative therapy exists yet. In search of a novel therapeutic antibody, we previously applied phage display with myeloma cell screening and developed TP15, a scFv targeting intercellular adhesion molecule 1 (ICAM-1/CD54). To more precisely evaluate the antibody's modes of action, fully human IgG1 antibody variants were generated bearing wild-type (MSH-TP15) or mutated Fc to either enhance (MSH-TP15 Fc-eng.) or prevent (MSH-TP15 Fc k.o.) Fc gamma receptor binding. Especially MSH-TP15 Fc-eng. induced potent antibody-dependent cell-mediated cytotoxicity (ADCC) against malignant plasma cells by efficiently recruiting NK cells and engaged macrophages for antibody-dependent cellular phagocytosis (ADCP) of tumor cells. Binding studies with truncated ICAM-1 demonstrated MSH-TP15 binding to ICAM-1 domain 1-2. Importantly, MSH-TP15 and MSH-TP15 Fc-eng. both prevented myeloma cell engraftment and significantly prolonged survival of mice in an intraperitoneal xenograft model. In the subcutaneous model MSH-TP15 Fc-eng. was superior to MSH-TP15, whereas MSH-TP15 Fc k.o. was not effective in both models - reflecting the importance of Fc-dependent mechanisms of action also in vivo. The efficient recruitment of immune cells and the potent anti-tumor activity of the Fc-engineered MSH-TP15 antibody hold significant potential for myeloma immunotherapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Renal fibrosis	Discovery	JP	Taisho Pharmaceutical Co., Ltd.	20 Oct 2023

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