Therapeutic Monoclonal Antibodies in Oncology

Levene, Adam P; Singh, Guminder; Palmieri, Carlo

doi:10.1177/014107680509800403

Cited by 45 publications

(30 citation statements)

References 51 publications

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“…For example, liposomes can be engineered to exhibit half-lives on the order of 6 h by modifying their size and surface characteristics (27). This is significantly faster than the circulation half-lives of antibodies (28). In particular for J591, blood clearance in patients was reported to be described by a double exponential decay with a fast half-life of less than 3 h (for 20% of administered radioactivity) and with a slower half-life of 44 h (for 80% of administered radioactivity) (29).…”

Section: Discussionmentioning

confidence: 99%

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

et al. 2013

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This study evaluates targeted liposomes loaded with the a-particle generator 225 Ac to selectively kill prostate-specific membrane antigen (PSMA)-expressing cells with the aim to assess their potential for targeted antivascular radiotherapy. Methods: In this study, PEGylated liposomes were loaded with 225 Ac and labeled with the mouse antihuman PSMA J591 antibody or with the A10 PSMA aptamer. The targeting selectivity, extent of internalization, and killing efficacy of liposomes were evaluated on monolayers of prostate cancer cells intrinsically expressing PSMA (human LNCaP and rat Mat-Lu cells) and on monolayers of HUVEC induced to express PSMA (induced HUVEC). Results: The loading efficiency of 225 Ac into preformed liposomes ranged from 58.0% 6 4.6% to 85.6% 6 11.7% of introduced radioactivity. The conjugation reactions resulted in approximately 17 6 2 J591 antibodies and 9 6 2 A10 aptamers per liposome. The average size of liposomes, 107 6 2 nm in diameter, was not affected by conjugation or loading. LNCaP cells exhibit 2:1:0.5 relative PSMA expression, compared with MatLu and induced HUVEC, respectively, based on flow cytometry detecting association of the J591 antibody. J591-labeled liposomes display higher levels of total specific binding to all cell lines than A10 aptamer-labeled liposomes. Specific cell association of targeted liposomes increases with incubation time. Cytotoxicity studies demonstrate that radiolabeled J591-labeled liposomes are most cytotoxic, with median lethal dose values, after 24 h of incubation, equal to 1.96 (5.3 · 10 25 ), 2.92 · 10 2 (7.9 · 10 23 ), and 2.33 · 10 1 Bq/mL (6.3 · 10 24 mCi/mL) for LNCaP, Mat-Lu, and induced HUVEC, respectively, which are comparable to the values for the radiolabeled J591 antibody. For A10 aptamer-labeled liposomes, the corresponding values are 3.70 · 10 1 (1.0 · 10 23 ), 1.85 · 10 3 (5.0 · 10 22 ), and 4.07 · 10 3 Bq/mL (1.1 · 10 21 mCi/mL), respectively. Conclusion: Our studies demonstrate that anti-PSMA-targeted liposomes loaded with 225 Ac selectively bind, become internalized, and kill PSMA-expressing cells including endothelial cells induced to express PSMA. These findings-combined with the unique ability of liposomes to be easily tuned, in terms of size and surface modification, for optimizing biodistributions-suggest the potential of PSMA-targeting liposomes encapsulating a-particle emitters for selective antivascular a radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

et al. 2013

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“…Lymphatics have an important role in the convective process by which proteins enter normal tissues. Antibodies often remain within the circulation for many days and, when given at high concentrations, eventually accumulate at effective levels within tumors (9). However, other types of antibody-based therapeutics such as immunotoxins, immunocytokines, and other immunoconjugates have much shorter lifetimes in the circulation and, consequently, their accumulation in tumors is impaired.…”

Section: Recombinant Immunotoxins Are Chimeric Proteins In Whichmentioning

confidence: 99%

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Zhang

Xiang

Hassan

et al. 2006

Clinical Cancer Research

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Purpose:To investigate the combined antitumor activity in mice of immunotoxin SS1P and Taxol.Methods: Immunodeficient mice were implanted with A431/K5 tumors expressing mesothelin. Established tumors were treated i.v. with immunotoxin SS1P alone, i.p. with Taxol alone, or with the two agents together. SS1P was radiolabeled with 111 In and used to study the effect of Taxol on its uptake by A431/K5 tumors. Results: Using doses at which either agent alone caused stabilization of tumor growth, the combination was synergistic causing long-lasting complete remissions in many animals. In contrast, synergy was not observed when the same cells were treated with these agents in vitro. Tumor uptake of 111In-SS1P was not affected by treatment withTaxol. Conclusion: The combination of Taxol and SS1P exerts a synergistic antitumor effect in animals but not in cell culture. This effect is not secondary to increased tumor uptake of the immunotoxin. Synergy could be due to improved immunotoxin distribution within the tumor or could involve factors released by other cell types in the tumors.

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“…The proposal 20 years ago that EGFR was an attractive target molecule for cancer therapy led to the development of several classes of anti-EGFR agents, including monoclonal antibodies (mAb) and receptor tyrosine kinase inhibitors (1 -3). One of these agents, cetuximab, is a chimeric mAb that binds to EGFR, blocks ligand binding, and thus prevents receptor activation and downstream signaling (4). Cetuximab was effective in phase II trials, and cotreatment with cetuximab and irinotecan gave better results than cetuximab alone (4 -7).…”

mentioning

confidence: 99%

Humanization of the Bispecific Epidermal Growth Factor Receptor × CD3 Diabody and Its Efficacy as a Potential Clinical Reagent

Asano

Sone

Makabe

et al. 2006

Clinical Cancer Research

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Purpose: Bispecific antibodies (BsAb) have been exploited as both cancer immunodiagnostics and cancer therapeutics and show promise in clinical trials of cancer imaging and therapy. For development of BsAbs as clinical reagents, we have focused on construction of small recombinant BsAbs, called bispecific diabodies. Here, we constructed and characterized a humanized bispecific diabody. Experimental Design: We have reported significant antitumor activity of an anti-epidermal growth factor receptor (EGFR) Â anti-CD3 bispecific diabody (Ex3) in in vitro cytotoxicity assays and in vivo. We humanized the Ex3 diabody (hEx3) by grafting the complementaritydetermining region and compared its biological properties with those of Ex3. We also tested its physiologic stability and ability to alter survival in xenografted mice. Results: The final yield of hEx3 was 10 times that of Ex3, and refolded hEx3 and Ex3 showed identical binding profiles in EGFR-positive cell lines and EGFR-transfected Chinese hamster ovary cells. hEx3 showed dose-dependent cytotoxicity to EGFR-positive cell lines, which could be specifically inhibited by parental monoclonal antibody IgGs against EGFR or CD3 antigens. The heterodimeric structure was retained in PBS for 6 months, and growth inhibition was maintained after incubation under physiologic conditions. Coadministration of hEx3 with T-LAK cells and interleukin-2 prolonged the survival of nude mice with human colon carcinoma. Conclusions:The humanized diabody hEx3 is an attractive molecule for cancer therapy and may provide important insights into the development of EGFR-based cancer-targeting reagents.

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Therapeutic Monoclonal Antibodies in Oncology

Cited by 45 publications

References 51 publications

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Humanization of the Bispecific Epidermal Growth Factor Receptor × CD3 Diabody and Its Efficacy as a Potential Clinical Reagent

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Therapeutic Monoclonal Antibodies in Oncology

Cited by 45 publications

References 51 publications

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with225Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with225Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice

Humanization of the Bispecific Epidermal Growth Factor Receptor × CD3 Diabody and Its Efficacy as a Potential Clinical Reagent

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Product

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Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer

Anti–Prostate-Specific Membrane Antigen Liposomes Loaded with²²⁵Ac for Potential Targeted Antivascular α-Particle Therapy of Cancer