Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma.

Abstract

We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T-cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell-to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies.

• Authors: Paul A Moore, Wenjun Zhang, G Jonah Rainey, Steve Burke, Hua Li, Ling Huang, Sergey Gorlatov, Maria Concetta Veri, Sudeepta Aggarwal, Yinhua Yang, Kalpana Shah, Linda Jin, Sunan Zhang, Leilei He, Tengfei Zhang, Valentina Ciccarone, Scott Koenig, Ezio Bonvini, Syd Johnson
• Journal: Blood (Blood) Vol. 117 Issue 17 Pg. 4542-51 (Apr 28 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21300981 (Publication Type: Journal Article)

Chemical References

• Antibodies, Bispecific
• Antigens, CD19
• CD3 Complex
• Fv protein, human
• Lymphokines
• Receptors, Antigen, T-Cell
• Sialoglycoproteins

Topics

• Animals
• Antibodies, Bispecific (immunology, pharmacology)
• Antigens, CD19 (immunology, metabolism)
• B-Lymphocytes (cytology, immunology)
• CD3 Complex (immunology, metabolism)
• Cell Communication (immunology)
• Cell Line, Tumor
• Female
• Humans
• Lymphokines (immunology)
• Lymphoma, B-Cell (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Sialoglycoproteins (immunology)
• T-Lymphocytes (cytology, immunology)
• Xenograft Model Antitumor Assays