Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease

Yazawa, Norihito; Hamaguchi, Yasuhito; Poe, Jonathan C.; Tedder, Thomas F.

doi:10.1073/pnas.0505539102

Cited by 110 publications

(117 citation statements)

References 53 publications

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“…Additionally, the pattern of human CD19 expression is similar to mouse CD19 in these animals (25)(26)(27), for example, on PCs where the mouse CD19 expression is downregulated and human CD19 expression is also downregulated on at least a portion of PCs (23). As a result, anti-human CD19 mAb depletes pre-B cells and mature B cells and also reduces basal serum IgM and IgG levels in hCD19Tg mice (28). MEDI551 was therefore used for these studies so that the results would be more directly translatable into human studies.…”

Section: G Rowing Evidence Suggests That B Cells and Abs Play An Impomentioning

confidence: 99%

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Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Chen

Ireland

Davis

et al. 2016

The Journal of Immunology

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The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein–specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb–treated mice, but they remained detectable in the CD20 mAb–treated mice. Interestingly, residual disease severity in the CD20 mAb–treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19+CD20− plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19+CD20− plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19+CD20− B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.

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Section: G Rowing Evidence Suggests That B Cells and Abs Play An Impomentioning

confidence: 99%

“…For analyzing CD19 and CD20 expression on CD138 + PCs, splenocytes and bone marrow cells from EAE mice at the peak of disease were stained with a human CD19 Ab (BV421 mouse antihuman CD19, clone HIB19, BD Biosciences), an unconjugated mouse CD20 Ab (clone MB20-11, isotype mIgG2a, MedImmune) (24,28), and other Abs to define PCs (IgD …”

Section: Flow Cytometrymentioning

confidence: 99%

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Chen

Ireland

Davis

et al. 2016

The Journal of Immunology

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“…15 Thus, the cHD37 and cHD37-DcVV MAbs were tested for the ability to interact with the human FccR and mediate ADCC using human NK or murine LAK as effector cells.…”

Section: Interaction With Human Fccr and Adccmentioning

confidence: 99%

“…[12][13][14] The clinical implications of CD19 as an immunotherapeutic target for cancer and autoimmune diseases have been demonstrated by using transgenic mice that express human CD19 molecules. 15 Several CD19-targeting approaches have been developed and evaluated in pre-clinical studies. Recently, a bispecific MAb targeting CD19 and CD3 to recruit T cells to kill CD19 þ tumor cells was evaluated in clinical trials and exhibited encouraging results.…”

mentioning

confidence: 99%

“…16 Anti-CD19 MAbs can induce growth arrest or death of tumor cells, recruit effector cells, reverse P-gp-mediated multidrug resistance, and deliver organic compounds, toxins and radioisotopes to target cells. 15,[17][18][19][20][21][22][23][24][25] In addition, HD37, a murine anti-human CD19 MAb conjugated to a deglycosylated ricin toxin A chain has effective anti-tumor activity against human pre-B ALL and Burkitt's lymphomas in SCID mice as well as in patients. 20,[24][25][26] The antitumor activity of some MAbs may be enhanced by increasing their valences.…”

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confidence: 99%

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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

Liu

Pop

Tsai

et al. 2010

Intl Journal of Cancer

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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 1 ) 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 1 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 1 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.

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Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia

Stackelberg

2011

New Agents for the Treatment of Acute Lymphoblastic Leukemia

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In 1975, Kohler et al. produced the first monoclonal antibodies (moAbs) by fusing a myeloma cell line with a specific antibody-producing B cell. This combined the unlimited growth potential of myeloma cells with the predetermined antibody specificity of normal immune spleen cells from an immunized mouse. The technique called somatic cell hybridization results in a hybridoma [1]. Humans receiving murine moAbs produce human anti-mouse antibodies (HAMA) leading to inactivation of the moAbs and allergic complications. The chimerization or humanization of moAbs via innovative recombinant DNA technology leads to a better tolerance to the compounds and has allowed for using the natural effector mechanisms of destroying with moAb-coated targets [2]. Whereas chimeric moAbs have antigenbinding parts (variable regions) of the mouse antibody and the effector parts (constant region, Fc) of a human antibody, in humanized compounds the mousederiving part of the moAb is reduced to the antigen-binding site (hypervariable region). The methodological approach to engineer the composition of moAbs is a broad and intensively developing field [3]. Structure of Monoclonal Antibodies (moAbs)A physiological IgG antibody consists of four polypeptide chains, two identical heavy chains and two identical light chains, which are covalently linked by interchain disulfide bonds. The chains have a variable (V) and a constant (C) region. The constant region of light chains consists of one C-domain, and the heavy chains have A. von Stackelberg (*) Pädiatrische Onkologie/Hämatologie,

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Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease

Cited by 110 publications

References 53 publications

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

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

Monoclonal Antibodies in Paediatric Acute Lymphoblastic Leukemia

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