Generation of a high‐producing clone of a humanized anti‐B‐cell lymphoma monoclonal antibody (hLL2)

Losman, Michele J.; Hansen, Hans J.; Dworak, Heather; Krishnan, Indira; Qu, Zhengxing; Shih, Lisa B.; Zeng, Li; Goldenberg, David M.; Leung, Shui‐on

doi:10.1002/(sici)1097-0142(19971215)80:12+<2660::aid-cncr43>3.3.co;2-i

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“…Although the assembly of synthetic antibody gene sequences is routine, generating constructs that can express high levels of immunoglobulin is not. To overcome the low production Typical of most plasmid vectors, we used a dihydrofolate reductase (dhfr; tetrahydrofolate dehydrogenase, E C 1.5.1.3) gene amplification strategy (8, 9) to enhance antibody production. The resulting construct could drive expression of a recombinant antibody gene to levels equaling or surpassing those of the best hybridomas.…”

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Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic‐progressive demyelinating disease

et al. 2002

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Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation. To demonstrate definitively that antibody is the biologically active component of patient serum, recombinant antibody was generated for evaluation in bioassays. The induction of remyelination in vivo requires milligram quantities of antibody. Consequently, an expression system was engineered to express high-titer, recombinant human IgM antibodies in vitro. A resulting recombinant antibody (rHIgM22) was evaluated for its ability to induce remyelination in the Theiler's virus mouse model of chronic-progressive demyelinating disease. We demonstrate that a single recombinant monoclonal antibody recapitulates the key characteristics of patient serum, including binding specificity, the induction of calcium signals in oligodendrocytes in vitro, and the induction of myelin repair within demyelinated plaques in vivo. The rHIgM22 antibody provides a new venue for the analysis of mechanisms governing remyelination and may prove useful in the treatment of demyelinating diseases.

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Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic‐progressive demyelinating disease

et al. 2002

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“…The humanized mAb, epratuzumab (hLL2 or IMMU-103) [18], [19], has demonstrated therapeutic activity in clinical trials of lymphoma and autoimmune disease, having treated over 1500 cases of non-Hodgkin lymphoma (NHL) [1], [20]–[25], acute lymphoblastic leukemias [26], Sjögren’s syndrome [27], and SLE [28]–[31]. Although epratuzumab has indicated clinical activity [1], [20]–[31], its mechanism of action (MOA) remains obscure.…”

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Anti-CD22/CD20 Bispecific Antibody with Enhanced Trogocytosis for Treatment of Lupus

2014

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The humanized anti-CD22 antibody, epratuzumab, has demonstrated therapeutic activity in clinical trials of lymphoma, leukemia and autoimmune diseases, treating currently over 1500 cases of non-Hodgkin lymphoma, acute lymphoblastic leukemias, Waldenström’s macroglobulinemia, Sjögren’s syndrome, and systemic lupus erythematosus. Because epratuzumab reduces on average only 35% of circulating B cells in patients, and has minimal antibody-dependent cellular cytotoxicity and negligible complement-dependent cytotoxicity when evaluated in vitro, its therapeutic activity may not result completely from B-cell depletion. We reported recently that epratuzumab mediates Fc/FcR-dependent membrane transfer from B cells to effector cells via trogocytosis, resulting in a substantial reduction of multiple BCR modulators, including CD22, CD19, CD21, and CD79b, as well as key cell adhesion molecules, including CD44, CD62L, and β7 integrin, on the surface of B cells in peripheral blood mononuclear cells obtained from normal donors or SLE patients. Rituximab has clinical activity in lupus, but failed to achieve primary endpoints in a Phase III trial. This is the first study of trogocytosis mediated by bispecific antibodies targeting neighboring cell-surface proteins, CD22, CD20, and CD19, as demonstrated by flow cytometry and immunofluorescence microscopy. We show that, compared to epratuzumab, a bispecific hexavalent antibody comprising epratuzumab and veltuzumab (humanized anti-CD20 mAb) exhibits enhanced trogocytosis resulting in major reductions in B-cell surface levels of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β7-integrin, and with considerably less immunocompromising B-cell depletion that would result with anti-CD20 mAbs such as veltuzumab or rituximab, given either alone or in combination with epratuzumab. A CD22/CD19 bispecific hexavalent antibody, which exhibited enhanced trogocytosis of some antigens and minimal B-cell depletion, may also be therapeutically useful. The bispecific antibody is a candidate for improved treatment of lupus and other autoimmune diseases, offering advantages over administration of the two parental antibodies in combination.

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Generation of a high‐producing clone of a humanized anti‐B‐cell lymphoma monoclonal antibody (hLL2)

Abstract: By means of gene amplification, the authors have generated a high-producing hLL2-IgG clone suitable for production of the quantity of antibody necessary for clinical diagnostic and therapeutic trials of NHL patients.

Cited by 2 publications

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Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic‐progressive demyelinating disease

Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic‐progressive demyelinating disease

Anti-CD22/CD20 Bispecific Antibody with Enhanced Trogocytosis for Treatment of Lupus

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