In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

Tassone, Pierfrancesco; Gozzini, Antonella; Goldmacher, Victor S.; Shammas, Masood A.; Whiteman, Kathleen R.; Carrasco, Daniel R.; Li, Cheng; Allam, Charles; Venuta, Salvatore; Anderson, Kenneth C.; Munshi, Nikhil C.

doi:10.1158/0008-5472.can-04-0142

Cited by 146 publications

(93 citation statements)

References 41 publications

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“…CD56 is expressed by a variety of cancers, including hematopoietic tumors, neuroendocrine tumors (e.g., small cell lung cancer), multiple myeloma, neuroblastoma, and ovarian cancer (64). Lorvotuzumab mertansine is a conjugate of the humanized monoclonal antibody huN901 and the maytansine derivative DM1 (65,66). It is currently in phase I/II (67,68).…”

Section: Targetsmentioning

confidence: 99%

Antibody Conjugate Therapeutics: Challenges and Potential

Teicher

Chari²

2011

Clinical Cancer Research

373

281

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Antibody conjugates are a diverse class of therapeutics consisting of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates is marked by hurdles that have been identified and overcome. Early conjugates used mouse antibodies; cytotoxic agents that were immunogenic (proteins), too toxic, or not sufficiently potent; and linkers that were not sufficiently stable in circulation. Investigators have explored 4 main avenues using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small-molecule drug conjugates, and antibody-enzyme conjugates administered along with small-molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and nearly 20 antibody conjugates are currently in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for cancer patients.

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Section: Targetsmentioning

confidence: 99%

Antibody Conjugate Therapeutics: Challenges and Potential

Teicher

Chari²

2011

Clinical Cancer Research

373

281

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“…A number of maytansinoid ADCs have been characterized with demonstrated preclinical activity and more recently, clinical activity, targeting several different cell surface tumor antigens including CD19, PSMA, CD33, CD138, and CD56 (31)(32)(33)(34)(35). Importantly, Kadcyla® (ado-trastuzumab emtansine) carries an anti-mitotic maytansine derivative while Adcetris® (brentuximab vedotin) is conjugated to an auristatin derivative (36,37).…”

Section: Payloadsmentioning

confidence: 99%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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“…Accordingly, therapeutic antibodies against a variety of myeloma antigens, such as CD40, 8 CD56, 9 CD138, 10 and CD20, 11 have been developed; however, none of these therapeutics has, so far, proven to be clinically effective and alternative myeloma surface molecules are urgently needed as potential targets.…”

Section: Introductionmentioning

confidence: 99%

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

Atanackovic¹,

Panse²,

Hildebrandt³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundTo date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myelomaspecific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Design and MethodsPotential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. ResultsOur screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement-and cell-mediated lysis of myeloma cells. ConclusionsOur results demonstrate that the immunoreceptor CD229 is specifically over-expressed on myeloma cells including their clonogenic precursors and contributes to their malignant phenotype. Monoclonal antibodies against this protein may represent a promising diagnostic and immunotherapeutic instrument in this disease. Haematologica 2011;96(10):1512-1520. doi:10.3324/haematol.2010 Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

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In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

Cited by 146 publications

References 41 publications

Antibody Conjugate Therapeutics: Challenges and Potential

Antibody Conjugate Therapeutics: Challenges and Potential

Antibody Drug Conjugates: Preclinical Considerations

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

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