A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.

This corrects the article DOI: 10.1038/leu.2016.388.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct.

Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N=23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E:T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E:T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.

Preclinical data for Droloxifene.

The new antiestrogen Droloxifene has a 10-60-fold higher binding affinity to the estrogen receptor (ER) compared to the related compound Tamoxifen. A similar relationship was found in growth inhibition studies which showed that Droloxifene inhibited the different ER positive human breast cancer cells more effectively than Tamoxifen, predominantly in drug concentrations which are found in humans during therapy. As another consequence of the high stability of the complex formed by Droloxifene binding to the ER, intermittent exposures with clinically relevant concentrations of Droloxifene brought about effective growth inhibition of human ER positive tumor cells even after short-term application. Droloxifene was found, like Tamoxifen, to block human breast cancer cells in G1-phase of the cell cycle. Moreover, cell-cycle data confirmed the superior growth-inhibiting potency of Droloxifene compared to Tamoxifen. Droloxifene was also found to effectively induce expression of the negative growth factor TGF-beta, to inhibit IGF-I stimulated cell growth and to prevent estrogen-stimulated proto-oncogene c-myc expression. Unlike Tamoxifen, Droloxifene is a potent inhibitor of protein biosynthesis in ER-positive breast cancer cells at physiologically relevant concentrations. Lower estrogenic and higher antiestrogenic effects on immature rat uterus indicate a higher therapeutic index for Droloxifene compared to Tamoxifen. In vivo, Droloxifene displayed increased growth inhibition of different tumors of animal (R3230AC and 13762) and human origin (T61). Furthermore, it was found that the two structurally similar drugs differ in their toxicologic characteristics in the following important respects: Droloxifene is devoid of any in vivo or in vitro carcinogenic or mutagenic effects, whereas Tamoxifen causes liver tumors in rats, induces DNA adduct formation in rats and hamsters and shows transforming activity in SHE-cells (Syrian hamster embryo fibroblasts). Considerably less toxicity and a lower level of intrinsic estrogenicity was observed even after maximum long-term exposure of different animal species to Droloxifene, in comparison with Tamoxifen. Therefore, it can be assumed that Droloxifene may represent an important step forward in the treatment of mammary carcinomas in women through its better tolerability and increased efficacy compared with Tamoxifen. For long-term adjuvant or preventive treatment of breast cancer, Droloxifene may well be the safer choice.

The hypolipidemic effect of lifibrol during a long term treatment of pigs.

We investigated the hypolipidemic property of lifibrol in male and female minipigs in a long term trial over a treatment period of 6 months. Oral dosages between 12.5 mg/kg BW and 100 mg/kg BW lifibrol resulted in a strong reduction of serum cholesterol after only two weeks of treatment. The hypocholesterolemic effect was not counterbalanced and reached -76% at the end of the trial in the male pigs and -70% in the female pigs (100 mg/kg BW lifibrol). The reduction of serum cholesterol was mainly brought about by the reduction of LDL-cholesterol. Serum triglycerides seemed to be less influenced by lifibrol than serum cholesterol. The application of lifibrol had no significant influence on the weight gain of the pigs and did not alter the serum levels of AST and ALT. Lifibrol was well tolerated and the animals showed no symptoms of incompatibility.

[Realization of an online connection of laboratory apparatus with personal computers]. / Realisierung einer Online-Verbindung von Laborgeräten mit Personalcomputern.

Online data transfer from laboratory equipment to personal computer is more and more accepted as standard for animal experiments. This paper deals with the connection of the laboratory devices to the computer by using the serial RS-232C interface. Both the simplex and the duplex mode of data transfer are described as well as a fundamental concept of data handling in BASIC.

[ONLINE: program for online connection of laboratory apparatus with personal computers with special reference to the requirements of toxicological animal studies]. / ONLINE: Programm zur Online-Verbindung von Laborgeräten mit Personalcomputern unter besonderer Berücksichtigung der Anforderungen toxikologischer Tierstudien.

This paper deals with ONLINE, a program for interfacing laboratory devices with personal computers (PC) via RS-232C. ONLINE was used in our department of toxicology for the evaluation of animal weights and for data transfer from a hematology analyzer to the PC. The program allows simplex as well as duplex connection and supports the programming of communication parameters for the data transfer when using the RS-232C. Files can be generated for the uptake of data up to 100,000 data points. Selected parts of these files can be used for the calculation of descriptive statistical parameters. ONLINE requires a computer compatible to MS-DOS with at least 256 kBytes RAM and with both a serial and a parallel port.