Chimeric, divalent and tetravalent anti-CD19 monoclonal antibodies with potent in vitro and in vivo antitumor activity against human B-cell lymphoma and pre-B acute lymphoblastic leukemia cell lines.
CD19 is an attractive therapeutic target for treating human B-cell tumors. In our study, chimeric (c) divalent (cHD37) and tetravalent (cHD37-DcVV) anti-CD19 monoclonal antibodies (MAbs) were constructed, expressed and evaluated for their binding to human 19-positive (CD19(+)) tumor cell lines. They were also tested for proapoptotic activity and the ability to mediate effector functions. The antitumor activity of these MAbs was further tested in mice xenografted with the CD19(+) Burkitt's lymphoma cell line, Daudi or the pre-B acute lymphoblastic leukemia (ALL) cell line, NALM-6. The cHD37 and cHD37-DcVV MAbs exhibited specific binding and comparable proapoptotic activity on CD19(+) tumor cell lines in vitro. In addition, the cHD37 and cHD37-DcVV MAbs were similar in their ability to mediate antibody-dependent cell-mediated phagocytosis (ADCP). However, the tetravalent cHD37-DcVV MAb bound more avidly, had a slower dissociation rate, and did not internalize as well. It also had enhanced antibody-dependent cellular cytotoxicity (ADCC) with human but not murine effector cells. The cHD37 and cHD37-DcVV MAbs exhibited comparable affinity for the human neonatal Fc receptor (FcRn) and similar pharmacokinetics (PKs) in mice. Moreover, all the HD37 constructs were similar in extending the survival of mice xenografted with Daudi or NALM-6 tumor cells. Therefore, the cHD37 and cHD37-DcVV MAbs have potent antitumor activity and should be further developed for use in humans. Although not evident in mice, due to its increased ability to mediate ADCC with human but not mouse effector cells, the cHD37-DcVV MAb should have superior therapeutic efficacy in humans.
Liu
Xiao-Yun
XY
The Cancer Immunobiology Center, The University of Texas Southwestern Medical Center at Dallas, Texas 75390-8576, USA.
Pop
Laurentiu M
LM
Tsai
Lydia
L
Pop
Iliodora V
IV
Vitetta
Ellen S
ES
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000737:chemistry / Q000276:immunology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000970:Antineoplastic Agents