maytansine and Multiple-Myeloma

Lorvotuzumab mertansine (LM) is an ADC composed of an anti CD56 humanized N901 monoclonal antibody conjugated via a stable disulfide linker to the maytansinoid DM1. CD56 is expressed in up to 78% of multiple myelomas. LM displays antitumor activity in preclinical models of multiple myeloma. In a phase I study of MM, the MTD of single-agent LM was 112 mg/m². The dose-limiting toxicities were grade 3 fatigue and grade 3 acute, reversible, renal failure. 2 PRs and 4 MRs were observed at various dose levels starting at 60 mg/m². Building on the single agent experience, a phase II study of LM in combination with lenalidomide and dexamethasone was conducted. The optimal dose of LM was 75 mg/m² in the combination. The ORR was 56.4%. The most common treatment-related AE was peripheral neuropathy (PN), mostly grade 2 or less, with the majority of patients having a grade 1 PN at baseline. Continued evaluation of optimal dosing levels and schedules will be important to better define the utility of this promising treatment.

Topics: Antibodies, Monoclonal; CD56 Antigen; Humans; Immunoconjugates; Maytansine; Multiple Myeloma

Despite therapeutic advancements that have significantly improved outcomes in multiple myeloma (MM), it remains an incurable disease. Patients with relapsed and/or refractory MM have an aggressive disease course, with inferior outcomes, necessitating the need for agents with novel therapeutic mechanisms. We present the results of a completed phase I trial of single-agent lorvotuzumab mertansine, a unique antibody-drug conjugate targeting CD56, which is frequently expressed in MM.. Thirty-seven patients with relapsed MM were enrolled in a dose-escalation phase I clinical trial to determine the maximum tolerated dose of lorvotuzumab mertansine (112 mg/m. Despite a high proportion of patients with relapsed and/or refractory MM (56.8%), stable disease or better was noted in 42.9% of patients, and these patients had a long duration of response (median, 15.5 months). The adverse event profile was favorable, with a low incidence of grade 3/4 adverse events and no infusion-related reactions. No humoral responses were detected against the study drug.. This completed phase I trial of single-agent lorvotuzumab mertansine provides ample evidence of safety and signals of clinical activity for this agent, warranting its further clinical development as part of combination regimens for the management of MM.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; CD56 Antigen; Female; Humans; Male; Maytansine; Middle Aged; Multiple Myeloma; Recurrence

Here, we report a CD138 receptor targeting liposomal formulation (TNP[Prodrug-4]) that achieved efficacious tumor growth inhibition in treating multiple myeloma by overcoming the dose limiting severe toxicity issues of a highly potent drug, Mertansine (DM1). Despite the promising potential to treat various cancers, due to poor solubility and pharmacokinetic profile, DM1's translation to the clinic has been unsatisfactory. We hypothesized that the optimal prodrug chemistry would promote efficient loading of the prodrug into targeted nanoparticles and achieve controlled release following endocytosis by the cancer cells, consequently, accomplish the most potent tumor growth inhibition. We evaluated four functional linker chemistries for synthesizing DM1-Prodrug molecules and evaluated their stability and cancer cell toxicity in vitro. It was determined that the phosphodiester moiety, as part of nanoparticle formulations, demonstrated most favorable characteristics with an IC

Topics: Cell Line, Tumor; Humans; Liposomes; Maytansine; Multiple Myeloma; Nanoparticles; Peptides; Prodrugs

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Carcinoma, Ductal, Breast; Corneal Diseases; Diagnostic Techniques, Ophthalmological; Drug Monitoring; Epithelium, Corneal; Humans; Immunoconjugates; Maytansine; Mesothelioma, Malignant; Multiple Myeloma; Photophobia; Vision Disorders

Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively. Specifically, CD38-targeting daratumumab-resistant MM cells were highly susceptible to VIS832 which, unlike daratumumab, spares NK cells. Superior maximal cytolysis of VIS832 vs. daratumumab corresponded to higher CD138 vs. CD38 levels in MM cells. Furthermore, VIS832 acted synergistically with lenalidomide or bortezomib to deplete MM cells. Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy (P < 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.

Topics: Animals; Antineoplastic Agents, Immunological; Bortezomib; Cell Line, Tumor; Drug Synergism; Humans; Immunoconjugates; Maytansine; Mice; Mice, SCID; Multiple Myeloma; Neoplasm Proteins; Syndecan-1; Xenograft Model Antitumor Assays

Indatuximab ravtansine is a monoclonal antibody-linked cytotoxic agent that specifically targets CD138-expressing cells. Monotherapy has been shown to significantly inhibit multiple myeloma tumour growth in vivo and improve host survival. Here, we show that in most cell lines tested, indatuximab ravtansine acts additively or even synergistically with clinically approved therapies for treatment of multiple myeloma. In addition, in vivo mouse xenograft models confirmed the activity of indatuximab ravtansine in combination with lenalidamide and lenalidomide/dexamethasone. Indatuximab ravtansine may therefore be a suitable combination partner for multiple myeloma, and a clinical study is ongoing.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Evaluation, Preclinical; Humans; Immunoconjugates; Lenalidomide; Maytansine; Mice; Multiple Myeloma; Syndecan-1; Thalidomide

We investigated the antitumor effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo.. We examined the growth inhibitory effect of BT062-SPDB-DM4, BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells from MM patients. We also examined in vivo activity of these agents in murine MM cell xenograft model of human and severe combined immunodeficient (SCID) mice bearing implant bone chips injected with human MM cells (SCID-hu model).. Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines and primary tumor cells from MM patients without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G(2)-M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The coculture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity of immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model.. These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents, Phytogenic; Bone Marrow Cells; Cell Line, Tumor; Humans; Immunoconjugates; Insulin-Like Growth Factor I; Interleukin-6; Maytansine; Mice; Mice, SCID; Multiple Myeloma; Stromal Cells; Syndecan-1; Xenograft Model Antitumor Assays

HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.

Topics: Animals; Antibodies, Monoclonal; CD56 Antigen; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Humans; Immunotoxins; Male; Maytansine; Mice; Mice, SCID; Multiple Myeloma; Neural Cell Adhesion Molecules; Xenograft Model Antitumor Assays

We tested the in vitro and in vivo antitumor activity of the maytansinoid DM1 (N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine), a potent antimicrotubule agent, covalently linked to the murine monoclonal antibody (mAb) B-B4 targeting syndecan-1 (CD138). We evaluated the in vitro activity of B-B4-DM1 against a panel of CD138(+) and CD138(-) cell lines, as well as CD138(+) patient multiple myeloma (MM) cells. Treatment with B-B4-DM1 selectively decreased growth and survival of MM cell lines, patient MM cells, and MM cells adherent to bone marrow stromal cells. We further examined the activity of B-B4-DM1 in 3 human MM models in mice: (1) severe combined immunodeficient (SCID) mice bearing subcutaneous xenografts; (2) SCID mice bearing green fluorescent protein-positive (GFP(+)) xenografts; and (3) SCID mice implanted with human fetal bone (SCID-hu) and subsequently injected with patient MM cells. Tumor regression and inhibition of tumor growth, improvement in overall survival, and reduction in levels of circulating human paraprotein were observed in mice treated with B-B4-DM1. Although immunohistochemical analysis demonstrates restricted CD138 expression in human tissues, the lack of B-B4 reactivity with mouse tissues precludes evaluation of its toxicity in these models. In conclusion, B-B4-DM1 is a potent anti-MM agent that kills cells in an antigen-dependent manner in vitro and mediates in vivo antitumor activity at doses that are well tolerated, providing the rationale for clinical trials of this immunoconjugate in MM.

Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Case-Control Studies; Cell Proliferation; Cell Survival; Humans; Immunoconjugates; Male; Maytansine; Membrane Glycoproteins; Mice; Mice, SCID; Multiple Myeloma; Neoplasm Transplantation; Proteoglycans; Survival Rate; Syndecan-1; Syndecans; Transplantation, Heterologous; Tumor Cells, Cultured