National Engineering Research Center for Antibody Medicine

Shanghai, China

National Engineering Research Center for Antibody Medicine

Shanghai, China
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Zhang Y.,China Pharmaceutical University | Li H.,China Pharmaceutical University | Li H.,301 General Hospital Cancer Center | Li H.,National Engineering Research Center for Antibody Medicine | And 13 more authors.
International Journal of Pharmaceutics | Year: 2010

Cationic liposomes (CLs) composed of 3β-[N-(N′,N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and dioleoylphosphatidylethanolamine (DOPE) (DC-Chol/DOPE liposomes) have been classified as one of the most efficient gene delivery systems. Our study aims to examine the effect of the molar ratio of DC-Chol/DOPE, PEGylation and serum on the pDNA (plasmid pDNA) and siRNA (small interfering RNA) transfection of DC-Chol/DOPE liposomes. The results showed that the most efficient DC-Chol/DOPE liposomes for pDNA or siRNA delivery were at a 1:2 or 1:1 molar ratio of DC-Chol/DOPE, respectively. The transfection efficiency of DC-Chol/DOPE liposomes increased along with increased weight ratio of DC-Chol/siRNA. However, the pDNA transfection efficiency decreased along with increased weight ratio of DC-Chol/pDNA from 3/1. As expected, PEGylation decreased siRNA and pDNA transfection efficiency of DC-Chol/DOPE liposomes. In PEGylated DC-Chol/DOPE liposomes, increased weight ratio of DC-Chol/pDNA from 3/1 did not lead to higher pDNA transfection efficiency, whereas increased weight ratio of DC-Chol/siRNA resulted in increased siRNA transfection efficiency. Furthermore, the serum did not significantly inhibit the pDNA and siRNA transfection efficiency of DC-Chol/DOPE liposomes. In conclusion, our results elucidated the influence factors of DC-Chol/DOPE liposome transfection and would reveal that siRNA and pDNA transfection mechanisms were different in DC-Chol/DOPE liposomes. © 2010 Elsevier B.V.

Li W.,International Medical University | Li W.,National Engineering Research Center for Antibody Medicine | Feng S.,National University of Singapore | Guo Y.,International Medical University | And 2 more authors.
Nanomedicine | Year: 2012

Block copolymer micelles have shown great potential in drug delivery systems, not only for overcoming the drawbacks of small agents such as water insolubility and wide distribution in normal tissues, but also for avoiding traditional nanoparticle formulation shortcomings, including in vivo instability and fast clearance from the blood. However, for translating micellar formulations to clinical practice, it is essential to overcome the many in vivo obstacles. Surmounting these barriers strongly depends on micellar physicochemical properties, which can be further optimized by the unique physiological aspects of solid tumors such as low pH, high temperature and the presence of abnormal vessels. Herein, based on the Flory parameter and scaling theory, the fundamental mechanisms and correlations in vitro/in vivo between self assembly, drug loading and release, stability, intracellular delivery and in vivo distribution, as well as micellar composition, size and microstructural tailoring are systematically revisited. The methods for enhancing micellar performance in solid tumors were consequently proposed through well-defined core-corona structure tailoring. © 2012 Future Medicine Ltd.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Chen H.,International Medical University | Song H.,Liaocheng University | And 13 more authors.
Mini-Reviews in Medicinal Chemistry | Year: 2013

Monoclonal antibodies (mAbs) or their derivatives are often used as the targeted ligands in the ligand targeted liposomes (LTLs). LTLs modified with mAbs or their derivatives are defined as immunoliposomes. Immunoliposomes can be designed to improve the pharmacological properties of conventional drugs. The development of immunoliposomes, which perfectly combines antibody engineering and liposomes, is becoming a possible state-of-the-art in liposome research. This review discusses the recent characterization and therapeutic effects of immunoliposomes in cancer therapy. The recent advances in the field of immunoliposomes for the treatment of cancer are summarized as follows: antibody engineering, current antibody conjugation strategies, characterization and therapeutic effects of immunoliposomes and the future perspective of immunoliposomes. Although antibody targeted immunoliposomes are being developed rapidly, there has been still a number of hot spots in research that require sustained effort for success. It is reasonable to predict that immunoliposomes will be approved for clinic use, and patients will benefit much from this cancer targeted therapy. © 2013 Bentham Science Publishers.

Li B.,International Medical University | Li B.,National Engineering Research Center for Antibody Medicine | Zhao L.,International Medical University | Wang C.,Shanghai JiaoTong University | And 10 more authors.
Journal of Biological Chemistry | Year: 2010

Understanding the evolutionary mechanism that acts at the interfaces of protein-protein complexes is a fundamental issue with high interest for delineating the macromolecular complexes and networks responsible for regulation and complexity in biological systems. To investigate whether the evolution of protein-protein interface acts in a similar way as antibody affinity maturation, we incorporated evolutionary information derived from antibody affinity maturation with common simulation techniques to evaluate prediction success rates of the computational method in affinity improvement in four different systems: antibody-receptor, antibody-peptide, receptor-membrane ligand, and receptor-soluble ligand. It was interesting to find that the same evolutionary information could improve the prediction success rates in all the four protein-protein complexes with an exceptional high accuracy (>57%). One of the most striking findings in our present study is that not only in the antibody-combining site but in other protein-protein interfaces almost all of the affinity-enhancing mutations are located at the germline hotspot sequences (RGYW or WA), indicating that DNA hot spot mechanisms may be widely used in the evolution of protein-protein interfaces. Our data suggest that the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions. Additionally, our data indicate that classical simulation techniques incorporating the evolutionary information derived from in vivo antibody affinity maturation can be utilized as a powerful tool to improve the binding affinity of protein-protein complex with a high accuracy. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Li B.,International Medical University | Li B.,National Engineering Research Center for Antibody Medicine | Li B.,State Key Laboratory of Antibody Medicine and Targeted Therapy | Li B.,General Hospital Cancer Center | And 26 more authors.
Cancer Research | Year: 2013

The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab- resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. © 2013 American Association for Cancer Research.

Wang S.,Shanghai JiaoTong University | Chen C.,Shanghai JiaoTong University | Meng Y.,International Medical University | Hu S.,International Medical University | And 11 more authors.
Cancer Letters | Year: 2012

Despite the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, less than 35% of patients with ErbB2-overexpressing breast cancer respond to the treatment. Here we engineered an anti-EGFR/ErbB2 bispecific antibody (TC-BsAb) using trastuzumab and cetuximab, an anti-EGFR chimeric antibody. TC-BsAb treatment led to internalization of both EGFR and ErbB2, whereas trastuzumab and cetuximab, either alone or in combination, failed to induce ErbB2 internalization. Both in vitro and in vivo experiments indicated that TC-BsAb was significantly more potent in inhibiting the growth of breast cancer cell lines than trastuzumab, cetuximab, and trastuzumab plus cetuximab, suggesting its potential use for treating breast cancer. © 2012 Elsevier Ireland Ltd.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Liu W.,Shanghai University College of Sciences | Xia Y.,International Medical University | And 22 more authors.
Biomaterials | Year: 2011

The LPD (liposome-polycation-DNA complex) is an effective nanovector for systemically small interfering RNA (siRNA) delivery which was well characterized previously. However, little effort was spend on the development of targeted LPD conjugated with tumor specific antibody (TLPD) which would be potent in promoting siRNA delivery in tumor. Here, we prepared TLPD through a self-assembling process followed by anti-EGFR antibody conjugation. The effect of antibody type, conjugation strategy and amount on the physicochemical and biological properties of TLPD was investigated. We obtained optimized TLPD conjugated with anti-EGFR Fab' by conventional conjugation (TLPD-FCC), which possessed a small size around 150. nm and superior in vitro stability. Compared with nontargeted LPD (NTLPD), TLPD-FCC showed significantly enhanced binding affinity and luciferase gene silencing activity in EGFR overexpressing MDA-MB-231 breast cancer cells in vitro. Moreover, the in vivo accumulation of TLPD-FCC was obviously higher than that of NTLPD in MDA-MB-231 tumor 24. h post intravenous injection. The promoted uptake of TLPD-FCC in MDA-MB-231 tumor was further confirmed by confocal microscopy. Notably, three intravenous injections of siRNA in TLPD-FCC significantly silenced luciferase expression by ∼20%, whereas NTLPD showed little effect. All these results suggested that our TLPD-FCC have a great potential in delivering siRNA to EGFR overexpressing breast cancers. © 2011 Elsevier Ltd.

Li W.,International Medical University | Li W.,National Engineering Research Center for Antibody Medicine | Li J.,International Medical University | Gao J.,International Medical University | And 17 more authors.
Biomaterials | Year: 2011

Focusing on high temperature and low pH of tumor tissue, we prepared temperature and pH responsive poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-b-lacitde) (PID118-b-PLA59) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-b-ε-caprolactone) (PID118-b-PCL60) diblock copolymers with symmetric hydrophobic blocks by the reversible addition-fragmentation chain transfer (RAFT). The corresponding dual functional polymeric micelles were fabricated by dialysis methods. Their well-defined core-shell structure was characterized by 1H NMR in D2O and further confirmed by TEM. Their structural and physical chemistry properties such as diameters (D), core corona dimension (Rcore, Rshell), distribution (PDI), Mw, aggregation number (Nagg), second virial coefficient (A2), critical micellization concentration (CMC) and z-potential were firstly systemically investigated by dynamic and static laser light scattering. The volume phase transition temperature (VPTT) was around 40 °C above which the intracellular uptake of adriamycin (ADR) was significantly enhanced. Both flow cytometry and fluorescent microscopy showed that the ADR transported by these micelles was about 4 times higher than that by the commercial ADR formulation Taxotere®. In vitro cytotoxicity assay against N-87 cancer cell and confocal laser scanning microscopy (CLSM) also confirmed such promoting efficiency. In addition, it was interesting to find that cell surviving bounced back as T = 42 °C due to the inter-micellar aggregation. The well clarified mechanism strongly support that our finely tailored dual functional core-shell micelles are potent in enhancing cellular uptake and drug release. © 2011 Elsevier Ltd.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Chen H.,International Medical University | Yu Y.,International Medical University | And 16 more authors.
Biomaterials | Year: 2013

The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both invitro and invivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR. © 2013 Elsevier Ltd.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Yu Y.,International Medical University | Zhang Y.,Shanghai University College of Sciences | And 14 more authors.
Biomaterials | Year: 2012

The development of immunoliposomes for systemic siRNA (small interfering RNA) delivery is highly desired. We reported previously the development of targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' (TLPD-FCC) for siRNA delivery, which showed superior gene silencing activity in EGFR-overexpressing breast cancers. However, TLPD-FCC did not achieve satisfactory gene silencing activity in EGFR-overexpressing hepatocellular carcinoma (HCC). In this study, some modifications including increased antibody conjugation efficiency and reduced PEGylation degree were made to TLPD-FCC to increase gene silencing activity in HCC. The resultant optimized liposomes denoted as TLPD-FP75 efficiently bound and delivered to EGFR-overexpressing HCC, resulting in enhanced gene silencing activity compared to untargeted LPD (NTLPD-FP75). Tissue distribution in vivo revealed that the accumulation of TLPD-FP75 was higher than NTLPD-FP75 in orthotopic HCC model of mice. The promoted uptake of TLPD-FP75 in HCC cells was confirmed by confocal microscopy. To investigate the in vivo gene silencing activity, we administered TLPD-FP75 by intravenous injections into mice bearing orthotopic HCC. The results showed TLPD-FP75 potently suppressed luciferase expression, while little silencing was observed in NTLPD-FP75. TLPD-FP75 was demonstrated to possess potent gene silencing activity in HCC and will potentially increase the feasibility of HCC gene therapy. © 2011 Elsevier Ltd.

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