scholarly journals Development of a new high‐affinity human antibody with antitumor activity against solid and blood malignancies

2018 ◽  
Vol 32 (9) ◽  
pp. 5063-5077 ◽  
Author(s):  
Mouldy Sioud ◽  
Phuong Westby ◽  
Vlada Vasovic ◽  
Yngvar Fløisand ◽  
Qian Peng
Keyword(s):  
Antitumor Activity ◽  
Human Antibody ◽  
High Affinity

A High-Affinity Human Antibody That Targets Tumoral Blood Vessels

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 192-198 ◽  
Author(s):  
Lorenzo Tarli ◽  
Enrica Balza ◽  
Francesca Viti ◽  
Laura Borsi ◽  
Patrizia Castellani ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Small Cell Lung Carcinoma ◽  
Antibody Fragment ◽  
Human Colon ◽  
Experimental Models ◽  
Human Antibody ◽  
Cell Lung Carcinoma ◽  
High Affinity ◽  
Biodistribution Studies

Angiogenesis is a characteristic feature of many aggressive tumors and of other relevant disorders. Molecules capable of specifically binding to new-forming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportunities. We have studied the distribution of the ED-B oncofetal domain of fibronectin, a marker of angiogenesis, in four different tumor animal models: the F9 murine teratocarcinoma, SKMEL-28 human melanoma, N592 human small cell lung carcinoma, and C51 human colon carcinoma. In all of these experimental models we observed accumulation of the fibronectin isoform containing the ED-B domain around neovascular structures when the tumors were in the exponentially growing phase, but not in the slow-growing phase. Then we performed biodistribution studies in mice bearing a subcutaneously implanted F9 murine teratocarcinoma, using a high-affinity human antibody fragment (L19) directed against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti-lysozyme antibody fragment (D1.3), efficiently localizes in the tumoral vessels. The maximal dose of L19 accumulated in the tumor was observed 3 hours after injection (8.2% injected dose per gram). By virtue of the rapid clearance of the antibody fragment from the circulation, tumor-to-blood ratios of 1.9, 3.7, and 11.8 were obtained at 3, 5, and 24 hours, respectively. The tumor-targeting performance of L19 was not dose-dependent in the 0.7 to 10 μg range of injected antibody. The integral of the radioactivity localized in tumoral vessels over 24 hours was greater than 70-fold higher than the integral of the radioactivity in blood over the same time period, normalized per gram of tissue or fluid. These findings quantitatively show that new-forming blood vessels can selectively be targeted in vivo using specific antibodies, and suggest that L19 may be of clinical utility for the immunoscintigraphic detection of angiogenesis in patients.

scholarly journals High Affinity Human Antibody Fragments to Dengue Virus Non-Structural Protein 3

2010 ◽  
Vol 4 (11) ◽  
pp. e881 ◽  
Author(s):  
Nicole J. Moreland ◽  
Moon Y. F. Tay ◽  
Elfin Lim ◽  
Prasad N. Paradkar ◽  
Danny N. P. Doan ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Antibody Fragments ◽  
Human Antibody ◽  
Structural Protein ◽  
High Affinity

Effects of C7 substitutions in a high affinity microtubule-binding taxane on antitumor activity and drug transport

2011 ◽  
Vol 21 (16) ◽  
pp. 4852-4856 ◽  
Author(s):  
Xi Xiao ◽  
Ju Wu ◽  
Chiara Trigili ◽  
Hui Chen ◽  
Joseph W.K. Chu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Drug Transport ◽  
Microtubule Binding ◽  
High Affinity

scholarly journals Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus.

1990 ◽  
Vol 171 (1) ◽  
pp. 19-34 ◽  
Author(s):  
Y Ueki ◽  
I S Goldfarb ◽  
N Harindranath ◽  
M Gore ◽  
H Koprowski ◽  
...  
Keyword(s):  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
Rabies Virus ◽  
Gene Segment ◽  
Human Antibody ◽  
Cell Repertoire ◽  
High Affinity ◽  
Clonal Level ◽  
Vh Gene

We quantitated and characterized the changes in the human B cell repertoire, at the clonal level, before and after immunization with rabies virus. Moreover, we generated 10 monoclonal cell lines producing IgM, IgG, and IgA antibodies to the virus. We found that in healthy subjects, not previously exposed to the virus, nearly 2% of the circulating B lymphocytes were committed to the production of antibodies that bound the virus. These B cells expressed the surface CD5 molecule. The antibodies they produced were polyreactive IgM that displayed a relatively low affinity for the virus components (Kd, 1.0-2.4 x 10(-6) g/microliters). After immunization, different anti-virus (IgG and IgA) antibody-producing cells consistently appeared in the circulation and increased from less than 0.005% to greater than 10% of the total B cells committed to the production of IgG and IgA, respectively. Most of such B cells do not express CD5 and produce monoreactive antibodies of high affinity for rabies virus (Kd, 6.5 x 10(-9) to 1.2 x 10(-10) g/microliters). One of these IgG mAbs efficiently neutralized rabies virus in vitro and in vivo, as detailed elsewhere (Dietzschold, B., P. Casali, Y. Ueki, M. Gore, C. E. Rupprecht, A. L. Notkins, and H. Koprowski, manuscript submitted for publication). Hybridization experiments using probes specific for the different human V gene segment families revealed that cell precursors producing low affinity IgM binding to rabies virus utilized a restricted number of VH gene segments (i.e., only members of the VHIIIb subfamily), whereas cell precursors producing high affinity IgG and IgA to rabies virus utilized an assortment of different VH gene segments (i.e., members of the VHI, VHIII, VHIV, and VHVI families and VHIIIb subfamily). In conclusion, our studies show that EBV transformation in conjunction with limiting dilution technology and somatic cell hybridization techniques are useful methods for quantitating, at the B cell clonal level, the human antibody response to foreign Ags and for generating human mAbs of predetermined specificity and high affinity.

scholarly journals Identification of high-affinity anti-CD16A allotype-independent human antibody domains

2016 ◽  
Vol 101 (2) ◽  
pp. 281-289 ◽  
Author(s):  
Wei Li ◽  
Hongjia Yang ◽  
Dimiter S. Dimitrov
Keyword(s):  
Human Antibody ◽  
High Affinity

Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 119-119 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Philip W. Kantoff ◽  
Anthony E. Mega ◽  
Nicholas J. Vogelzang ◽  
Joe Stephenson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Phase 1 ◽  
Human Antibody ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Previously Treated ◽  
Dose Levels ◽  
Specific Membrane

119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Results: 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. Conclusions: PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. Clinical trial information: NCT01414283.

Sign in / Sign up

Export Citation Format

Share Document