BT062, a CD138-Specific Immunoconjugate, Demonstrates Superior In Vivo Anti-Myeloma Efficacy In Combination with Lenalidomide or Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3008-3008 ◽  
Author(s):  
Chantal Zuber ◽  
Benjamin Daelken ◽  
Silke Aigner ◽  
Thomas Haeder ◽  
Olga Ab ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Cytotoxic Activity ◽  
Plasma Cells ◽  
Body Weight Loss ◽  
Antagonistic Effect ◽  
Clinical Activity ◽  
Antibody Drug Conjugate

Abstract Abstract 3008 Background: BT062 represents a CD138 specific antibody-drug conjugate comprising a chimerized anti-CD138 antibody conjugated to maytansinoid (DM4), an inhibitor of tubulin polymerization. CD138 (syndecan-1) which is highly upregulated on neoplastic plasma cells, is currently used as a standard identification marker for multiple myeloma (MM) and provides therefore a promising target for therapeutic intervention in MM. We have previously reported that BT062 exerts high selective in vitro and in vivo cytotoxic activity against CD138 positive MM cells (Ikeda et al., Clin Cancer Res. 2009; 15(12)). Based on these results, a Phase I clinical trial has been conducted in relapsed/refractory MM patients, which demonstrated an acceptable toxicity profile after repeated administration of single doses up to 160 mg/m2, as well as first signs of clinical activity in heavily pretreated patients (Chanan-Khan et al., ASH 2009). Here, we investigated the anti-myeloma efficacy of BT062 when combined with clinically approved myeloma drugs in vitro and in experimental animals in vivo. Methods and Results: In vitro drug combination studies on different myeloma cell lines indicated that BT062 exerts synergistic cytotoxic activity when combined for example with lenalidomide on RPMI8226 myeloma cells. None of the myeloma drug combinations with BT062 resulted in a strong antagonistic effect. Lenalidomide and bortezomib, representing novel established anti-myeloma drugs, were further tested for combination with BT062 in SCID mice bearing MOLP-8 MM xenografts. A single intravenous injection of BT062 was active against these tumors (400 μg/kg: T/C = 7%, Log cell kill (LCK) = 2.7) without signs of toxicity (no body weight loss). Monotherapy of bortezomib (1 mg/kg, twice weekly for 2 weeks) was inactive against the MOLP-8 xenografts. However, when combined with BT062, a superior anti-tumor effect compared to BT062 monotherapy was observed: Single injection of BT062 at different concentrations (100 μg/kg, 200 μg/kg, 400 μg/kg) followed by i.v. administration of bortezomib (1 mg/kg, twice weekly for 2 weeks) resulted in a dose dependent inhibition of tumor cell growth (at 200 μg/kg: LCK = 2.0; T/C = 7%, at 400 μg/kg LCK = 3.2; T/C = 7%). No increased in toxicity have been observed in the combination treatment compared to each monotherapy. BT062 was further evaluated for combination with lenalidomide which was administered intraperitoneally, daily for 5 days (2 weeks in total): BT062 administered alone at concentrations of 400 μg/kg was highly active against the MOLP-8 tumors reflected by a LCK of 2.5 (T/C = 13%). A lower anti-tumor effect has been observed by lenalidomide monotherapy (LCK = 0.8, T/C = 38%). Combination of both drugs demonstrated superior anti-tumor activity compared to each monotherapy (e.g. 400 μg/kg BT062 + lenalidomide: LCK = 3.5; T/C = 8%). Remarkably, neither body weight loss nor symptoms of illness have been observed confirming that this combination is also well tolerated. Conclusion: These data demonstrate that BT062 is not only effective in MM monotherapy but represents further a promising candidate for combination with currently used anti-MM drugs such as bortezomib or lenalidomide. No increased toxicities have been observed in all in vivo xenograft studies indicating that BT062 combined with other cytotoxic compounds might be well tolerated in MM therapy. Interestingly, although BT062 has been administered as a single dose, the anti-tumor effect in combination with either bortezomib or lenalidomide was significantly enhanced. These data provide a rationale to further investigate BT062 in clinical combination trials. Disclosures: Zuber: Biotest AG: Employment. Daelken:Biotest AG: Employment. Aigner:Biotest AG: Employment. Haeder:Biotest AG: Employment. Ab:ImmunoGen, Inc.: Employment. Whiteman:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Osterroth:Biotest AG: Employment. Uherek:Biotest AG: Employment.

Effect of Hematoporphyrin « in Vivo » and « in Vitro » on ATPC+ Tumor Cells

1968 ◽  
Vol 54 (5) ◽  
pp. 361-368
Author(s):  
Giorgio Cittadini ◽  
Tommaso De Cata ◽  
Carlo Gubinelli
Keyword(s):  
Growth Rate ◽  
Weight Loss ◽  
Body Weight ◽  
Drug Toxicity ◽  
Body Weight Loss ◽  
Ascites Tumor ◽  
Once Daily ◽  
Fluid Interaction

ATPC+ ascites tumor transplants of different size were performed in NMRI mice. Hematoporphyrin chlorhydrate (Hp) was administered i.p. once daily during the seven days following transplantation. In the first series « in vivo » (1.9 x 106 cells; 0.1, 0.3, 0.9 mg of Hp), body weight, ascitogenic time (Tasc) and total ascitic volume (TV) were determined. Hematoporphyrin-treated animals showed, after the apprearance of the ascites, a body weight loss superior to controls, due to the drug toxicity caused by Hp vs. ascitic fluid interaction. Neither Tasc nor TV were significantly modified. In the second series « in vivo » (2.3 x 104 or 2.3 x 102 cells; 0.3 mg Hp), body weight loss was lower, Tasc was significantly increased and also the survival varied. In a third experiment ATPC+ cells were incubated « in vitro » with Hp in a range from 102 to 108 molecules/cell). No effect was observed on growth rate when the cells were transplanted into the host.

scholarly journals Rapid, Simple In Vivo Screen for New Drugs Active against Mycobacterium tuberculosis

2004 ◽  
Vol 48 (12) ◽  
pp. 4550-4555 ◽  
Author(s):  
Boris V. Nikonenko ◽  
Rowena Samala ◽  
Leo Einck ◽  
Carol A. Nacy
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Mycobacterium Tuberculosis ◽  
Standard Dose ◽  
Body Weight Loss ◽  
Drug Efficacy ◽  
New Drugs ◽  
Potential Marker

ABSTRACT We evaluated the use of a simple and easy-to-obtain potential marker of tuberculosis (TB) drug efficacy, body weight, and correlated weight loss or gain with the number of CFU of Mycobacterium tuberculosis in lungs and spleens of infected mice. C3H mice were infected intravenously with 106 CFU of virulent M. tuberculosis H37Rv, and body weight was evaluated for several weeks after infection. At day 20, infected untreated mice consistently lost more than 25% of their body weight. Chemotherapy with selected orally active anti-TB drugs was initiated 7 days following infection and continued for 13 days. Drugs that were administered daily by gavage included isoniazid (INH), ethambutol (EMB), rifampin (RIF), and moxifloxacin (MXF). At the most effective doses, each of these drugs inhibited bacterial growth and abolished infection-induced body weight loss. Chemotherapy with 1/10 the standard dose of INH determined in accepted long-term murine models of TB also prevented body weight loss, while chemotherapy with 1/10 the standard dose of RIF did not. With only 2 weeks of chemotherapy, we observed a good reverse correlation between CFU in lung or spleen and body weight of mice. The simple measurement of weight in TB-infected drug-treated mice required only a weight balance, and go/no-go drug efficacy data was available on day 20 without the necessity of prolonged drug treatment and long (3 weeks or more) in vitro culture times to obtain organ CFU values.

Leptin causes body weight loss in the absence of in vivo activities typical of cytokines of the IL-6 family

1998 ◽  
Vol 275 (3) ◽  
pp. R913-R919 ◽  
Author(s):  
Davide Agnello ◽  
Cristina Meazza ◽  
Christopher G. Rowan ◽  
Pia Villa ◽  
Pietro Ghezzi ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Body Weight Loss ◽  
Peripheral Blood Cell ◽  
Serum Corticosterone ◽  
Amyloid A ◽  
Cell Counts ◽  
Control Body ◽  
The One

To investigate if leptin shares in vivo activities with interleukin (IL)-6 family cytokines, it was tested in normal mice for the ability, after a single injection, to induce the acute-phase protein serum amyloid A, to potentiate the induction by IL-1 of serum corticosterone and IL-6, and to inhibit the induction by lipopolysaccharide of serum tumor necrosis factor and, after seven daily injections, to cause body weight loss and to change peripheral blood cell counts. At a 0.5 mg/kg dose, leptin caused body weight loss but did not show any of the other activities above. At a dose of 5 mg/kg, which also caused body weight loss, leptin potentiated the induction by IL-1 of serum corticosterone and IL-6 but did not show any other activity. In addition to causing body weight loss, leptin shows only some of the in vivo activities typical of IL-6 family cytokines and only if used at a dose that exceeds the one sufficient to affect body weight. In vivo, leptin seems to chiefly control body weight and not inflammatory or hematopoietic processes.

scholarly journals The Extract of Arctium lappa L. Fruit (Arctii Fructus) Improves Cancer-Induced Cachexia by Inhibiting Weight Loss of Skeletal Muscle and Adipose Tissue

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3195
Author(s):  
Yo-Han Han ◽  
Jeong-Geon Mun ◽  
Hee Dong Jeon ◽  
Dae Hwan Yoon ◽  
Byung-Min Choi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Uncoupling Protein ◽  
Body Weight Loss ◽  
In Vivo Experiments ◽  
Wasting Syndrome

Background: Cachexia induced by cancer is a systemic wasting syndrome and it accompanies continuous body weight loss with the exhaustion of skeletal muscle and adipose tissue. Cancer cachexia is not only a problem in itself, but it also reduces the effectiveness of treatments and deteriorates quality of life. However, effective treatments have not been found yet. Although Arctii Fructus (AF) has been studied about several pharmacological effects, there were no reports on its use in cancer cachexia. Methods: To induce cancer cachexia in mice, we inoculated CT-26 cells to BALB/c mice through subcutaneous injection and intraperitoneal injection. To mimic cancer cachexia in vitro, we used conditioned media (CM), which was CT-26 colon cancer cells cultured medium. Results: In in vivo experiments, AF suppressed expression of interleukin (IL)-6 and atrophy of skeletal muscle and adipose tissue. As a result, the administration of AF decreased mortality by preventing weight loss. In adipose tissue, AF decreased expression of uncoupling protein 1 (UCP1) by restoring AMP-activated protein kinase (AMPK) activation. In in vitro model, CM increased muscle degradation factors and decreased adipocytes differentiation factors. However, these tendencies were ameliorated by AF treatment in C2C12 myoblasts and 3T3-L1 cells. Conclusion: Taken together, our study demonstrated that AF could be a therapeutic supplement for patients suffering from cancer cachexia.

HM1.24/CD317-directed immunotoxin to eliminate malignant plasma cells in vitro and in vivo.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8604-8604
Author(s):  
Martin Gramatzki ◽  
Matthias Staudinger ◽  
Pia Glorius ◽  
Katja Klausz ◽  
Christian Kellner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasma Cells ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Target Structure ◽  
Single Chain ◽  
Pseudomonas Exotoxin A ◽  
Single Chain Fv

8604 Background: Targeted immunotherapy, based on antibodies against tumor-associated antigens, is a promising approach for the treatment of multiple myeloma (MM). Recently, antibody-based strategies delivering a toxic payload have documented impressive clinical activity in hematological malignancies. In particular, surface molecules overexpressed on malignant plasma cells and efficiently internalized represent promising targets for developing myeloma-directed immunoconstructs. Here, the identification of CD317 (HM1.24) as a potent target structure and the characterization of a novel CD317-directed single-chain immunotoxin, HM1.24-ETA', is described. Methods: Using a novel screening tool, a panel of antibodies against MM-associated antigens was evaluated for their ability to mediate antigen-dependent delivery of a truncated version of Pseudomonas exotoxin A (ETA’) to MM cells. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv antibody and ETA'. The anti-myeloma activity of the E. coli-expressed immunotoxin was evaluated in vitro and in a xenograft mouse model. Results: By screening a panel of antibodies including CD38, CS1, IL-6R, CD138 and CD317, CD317 was identified as a suitable receptor to deliver ETA’ to MM cells. The subsequently designed recombinant HM1.24-ETA' immunotoxin efficiently inhibited growth of MM cell lines with halfmaximal growth inhibition at concentrations of less than 1 nM. Antigen-specific MM cell killing occurred via induction of apoptosis. The proliferation of IL-6 dependent INA-6 cells was completely inhibited by HM1.24-ETA' even in the presence of bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA' strongly triggered apoptosis (up to 80%) in freshly isolated tumor cells from 7 out of 7 MM patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA' immunotoxin (p < 0.04). Conclusions: The HM1.24-ETA' immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of MM using immunoconjugates with toxic payloads.

A phase 2 study of galunisertib (TGF-Β R1 inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma (HCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4097-4097 ◽  
Author(s):  
Robin Kate Kelley ◽  
Edward Gane ◽  
Eric Assenat ◽  
Jurgen Siebler ◽  
Peter R. Galle ◽  
...  
Keyword(s):  
Weight Loss ◽  
Systemic Therapy ◽  
Primary Objective ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
In Vivo Models ◽  
Prior Systemic Therapy ◽  
Expansion Cohort

4097 Background: TGFβ signaling is associated with HCC progression. Inhibition of TGFβ R1 potentiates activity of sorafenib in in-vitro and in-vivo models. Here we report the clinical activity of galunisertib (G) plus sorafenib (S) in pts with incurable HCC and no prior systemic therapy. Methods: Eligibility criteria included incurable HCC with measurable disease per RECIST 1.1, no prior systemic therapy, Child Pugh A, ECOG PS ≤1.G was administered as 80 mg PO BID (lead-in Cohort 1) or 150 mg PO BID (lead-in Cohort 2 and expansion cohort), as intermittent dosing of 14 days on/off (28 days = 1 cycle). S was administered continuously as a 400 mg PO BID. Primary objective was to characterize time-to-progression (TTP) and biomarker changes in pts. Secondary objectives included evaluation of OS, PK, and toxicity (CTCAE v 4.0). Results: 47 pts were enrolled (Cohort 1 = 3, Cohort 2 and expansion cohort = 44). In the 150 mg BID cohort: Male = 88.6%; median age = 64 years; PS = 0/1, 81.8%/18.2%; etiology: hepatitis C = 34.1%, hepatitis B = 18.2%, alcohol = 20.5%, multiple = 13.6%; AFP≥200 µg/L = 50%; portal vein invasion = 34.1%. Incidence of AEs was similar between G dose levels. Overall in the 150mg BID cohort, treatment related AEs ( > 15%) were hand and foot syndrome (61.4%), diarrhea (40.9%), pruritus (22.7%), anemia and weight loss (20.5%), fatigue (29.5%), alopecia (18.2%), myalgia (22.7%), decrease in platelet count and nausea (15.9%). Two pts on 150 mg BID discontinued treatment due to study drug related AEs (anemia and weight loss). PK of G at 150 mg BID (n = 12) when co-administered with S, was similar to that observed in the G monotherapy study. G was rapidly absorbed and had an elimination half-life of approximately 8h. Median TTP (RECIST) was 4.1 (2.8, 5.5) months. OS, with a high censor rate of 55% was not mature at the time of this data cutoff. Median OS was 17.9 (14.8, NE) months. Conclusions: The combination of G plus S demonstrated acceptable safety and a meaningful OS of 17.9 months in an advanced HCC population. TTP was similar to S monotherapy in contemporary clinical trials though interpretation is limited by single arm design. Clinical trial information: NCT01246986.

scholarly journals Attenuation of proteolysis and muscle wasting by curcumin c3 complex in MAC16 colon tumour-bearing mice

2009 ◽  
Vol 102 (7) ◽  
pp. 967-975 ◽  
Author(s):  
Rafat A. Siddiqui ◽  
Samira Hassan ◽  
Kevin A. Harvey ◽  
Tamkeen Rasool ◽  
Tapas Das ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Fibres ◽  
Colon Tumour ◽  
Human Skeletal Muscle Cells ◽  
Curcumin C3 Complex

Muscle wasting or cachexia is caused by accelerated muscle protein breakdown via the ubiquitin–proteasome complex. We investigated the effect of curcumin c3 complex (curcumin c3) on attenuation of muscle proteolysis using in vitro and in vivo models. Our in vitro data indicate that curcumin c3 as low as 0·50 μg/ml was very effective in significantly inhibiting (30 %; P < 0·05) tyrosine release from human skeletal muscle cells, which reached a maximum level of inhibition of 60 % (P < 0·05) at 2·5 μg/ml. Curcumin c3 at 2·5 μg/ml also inhibited chymotrypsin-like 20S proteasome activity in these cells by 25 % (P < 0·05). For in vivo studies, we induced progressive muscle wasting in mice by implanting the MAC16 colon tumour. The in vivo data indicate that low doses of curcumin c3 (100 mg/kg body weight) was able to prevent weight loss in mice bearing MAC16 tumours whereas higher doses of curcumin c3 (250 mg/kg body weight) resulted in approximately 25 % (P < 0·05) weight gain as compared with the placebo-treated animals. Additionally, the effect of curcumin c3 on preventing and/or reversing cachexia was also evident by gains in the weight of the gastrocnemius muscle (30–58 %; P < 0·05) and with the increased size of the muscle fibres (30–65 %; P < 0·05). Furthermore, curcumin inhibited proteasome complex activity and variably reduced expression of muscle-specific ubiquitin ligases: atrogin-1/muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MURF-1). In conclusion, oral curcumin c3 results in the prevention and reversal of weight loss. The data imply that curcumin c3 may be an effective adjuvant therapy against cachexia.

scholarly journals Therapeutic Activity of Intramuscular Peramivir in Mice Infected with a Recombinant Influenza A/WSN/33 (H1N1) Virus Containing the H275Y Neuraminidase Mutation

2012 ◽  
Vol 56 (8) ◽  
pp. 4375-4380 ◽  
Author(s):  
Yacine Abed ◽  
Andrés Pizzorno ◽  
Guy Boivin
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Influenza A ◽  
Low Dose ◽  
Body Weight Loss ◽  
High Dose ◽  
Therapeutic Activity ◽  
Enzymatic Assays ◽  
Oseltamivir Resistance

ABSTRACTThe therapeutic activity of intramuscular (IM) peramivir was evaluated in mice infected with a recombinant influenza A/WSN/33 virus containing the H275Y neuraminidase (NA) mutation known to confer oseltamivir resistance. Regimens consisted of single (90 mg/kg of body weight) or multiple (45 mg/kg daily for 5 days) IM peramivir doses that were initiated 24 h or 48 h postinfection (p.i.). An oral oseltamivir regimen (1 or 10 mg/kg daily for 5 days) was used for comparison. Untreated animals had a mortality rate of 75% and showed a mean weight loss of 16.9% on day 5 p.i. When started at 24 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P< 0.001) and lung viral titers (LVT) (P< 0.001). A high dose (10 mg/kg) of oseltamivir initiated at 24 h p.i. also prevented mortality and significantly decreased weight loss (P< 0.05) and LVT (P< 0.001) compared to the untreated group results. In contrast, a low dose (1 mg/kg) of oseltamivir did not show any benefits. When started at 48 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P< 0.01) and LVT (P< 0.001) whereas low-dose or high-dose oseltamivir regimens had no effect on mortality rates, body weight loss, and LVT. Our results show that single-dose and multiple-dose IM peramivir regimens retain clinical and virological activities against the A/H1N1 H275Y variant despite some reduction in susceptibility when assessedin vitrousing enzymatic assays. IM peramivir could constitute an alternative for treatment of oseltamivir-resistant A/H1N1 infections, although additional studies are warranted to support such a recommendation.

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