Future of Monoclonal Antibodies in the Treatment of Hematologic Malignancies

Reff, Mitchell E.; Hariharan, Kandasamy; Braslawsky, Gary R.

doi:10.1177/107327480200900207

Cited by 70 publications

(41 citation statements)

References 95 publications

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“…Xenograft models of lymphoma in mice lacking FcR-g chain (12), or treated with neutralizing antibodies against mouse FcgR (13,14), have provided evidence for the contribution of ADCC to the therapeutic activity of rituximab. Data from several groups are also available indicating that B-lymphoblastoid cell lines and fresh B-lymphoma cells expressing CD20 can be killed by complement activated by rituximab (9,(15)(16)(17). The susceptibility of these cells to CDC is partly related to the expression level of CD20 on the cell surface, but it is also dependent on the ability of rituximab to induce the translocation of CD20 into lipid rafts (18), which favors the clustering of antibodies and, in turn, promotes C1q binding.…”

Section: Introductionmentioning

confidence: 99%

In vivoTargeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab

Macor¹,

Tripodo

Zorzet³

et al. 2007

Cancer Research

142

136

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An in vivo model of human CD20+ B-lymphoma was established in severe combined immunodeficiency mice to test the ability of human neutralizing miniantibodies to CD55 and CD59 (MB55 and MB59) to enhance the therapeutic effect of rituximab. The miniantibodies contained single-chain fragment variables and the hinge-CH2-CH3 domains of human IgG 1 . LCL2 cells were selected for the in vivo study among six B-lymphoma cell lines for their high susceptibility to rituximab-dependent complement-mediated killing enhanced by MB55 and MB59. The cells injected i.p. primarily colonized the liver and spleen, leading to the death of the animals within 30 to 40 days. Thirty percent of mice receiving biotin-labeled rituximab (25 Mg) i.p. on days 4 and 11 after cell injection survived to 120 days. Administration of biotin-labeled rituximab, followed by avidin (40 Mg) and biotin-labeled MB55-MB59 (100 Mg) at 4-h intervals after each injection resulted in the survival of 70% of mice. Surprisingly, 40% of mice survived after the sole injection of avidin and biotinlabeled MB55-MB59, an observation consistent with the in vitro data showing that the miniantibodies induced killing of f25% cells through antibody-dependent cell cytotoxicity. In conclusion, MB55 and MB59 targeted to tumor cells represent a valuable tool to enhance the therapeutic effect of rituximab and other complement-fixing antitumor antibodies.

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Section: Introductionmentioning

confidence: 99%

In vivoTargeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab

Macor¹,

Tripodo

Zorzet³

et al. 2007

Cancer Research

142

136

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“…3 However, application of recombinant DNA technology led to the development first of chimeric antibodies, then of partially humanized antibodies, 4,5 and ultimately of fully humanized antibodies. 6 Box 1 outlines the features of the different types in this progression. Radiochemistry and antibody engineering research were initially driven by the academic sector, followed by start-up biotech companies and subsequently larger pharmaceutical conglomerates.…”

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confidence: 99%

Therapeutic Monoclonal Antibodies in Oncology

2005

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“…The T 1/2 of a protein molecule correlates with its size relative to the threshold for glomerular filtration, which is estimated to be approximately 60 kDa. 87 Whereas intact IgG molecules (150 kDa) are too large to be filtered by the kidneys, smaller constructs may be subject to extensive renal clearance, resulting in shorter halflives. For example; small scFv fragments (30 kDa) have T 1/2 values in the range of 2 hours.…”

Section: Excretion Of Novel Ab Constructsmentioning

confidence: 99%

Antibody constructs in cancer therapy

Beckman

Weiner

Davis³

2007

Cancer

249

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Whereas over 85% of human cancers are solid tumors, of the 8 monoclonal antibodies (mAbs) currently approved for cancer therapy, 25% are directed at solid tumor surface antigens (Ags). This shortfall may be due to barriers to achieving adequate exposure in solid tumors. Advancements in tumor biology, protein engineering, and theoretical modeling of macromolecular transport are currently enabling identification of critical physical properties for antitumor Abs. It is now possible to structurally modify Abs or even replace full Abs with a plethora of Ab constructs. These constructs include Fab and Fab 0 2 fragments, scFvs, multivalent scFvs (e.g., diabodies and tribodies), minibodies (e.g., scFv-CH3 dimers), bispecific Abs, and camel variable functional heavy chain domains. The purpose of the article is to provide investigators with a conceptual framework for exploiting the recent scientific advancements. The focus is on 2 properties that govern tumor exposure: 1) physical properties that enable penetration of and retention by tumors, and 2) favorable plasma pharmacokinetics. It is demonstrated that manipulating molecular size, charge, valence, and binding affinity can optimize these properties.These manipulations hold the key to promoting tumor exposure and to ultimately creating successful Ab therapies for solid tumors.

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Future of Monoclonal Antibodies in the Treatment of Hematologic Malignancies

Abstract: A better appreciation of how MAbs are metabolized in the body and localized to tumors is resulting in the development of new antibody constructs with improved biodistribution profiles.

Cited by 70 publications

References 95 publications

In vivoTargeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab

In vivoTargeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab

Therapeutic Monoclonal Antibodies in Oncology

Antibody constructs in cancer therapy

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