Treatment of low-grade non-Hodgkin's lymphoma with continuous infusion of low-dose recombinant interleukin-2 in combination with the B-cell-specific monoclonal antibody CLB-CD19

Vlasveld, L. T.; Hekman, Annemarie; Vyth‐Dreese, Florry A.; Melief, C. J. M.; Sein, J.; Voordouw, A. C.; Dellemijn, Trees A. M.; Rankin, Elaine M.

doi:10.1007/bf01517234

Cited by 20 publications

(17 citation statements)

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“…Although early studies showed that unmodified anti-CD19 antibodies induced B-cell depletion, their clinical efficacy was limited (8,15), and consequently, clinical trials focused on anti-CD19 immunotoxin conjugates (10,39). To maximize the cytotoxic potential of an unmodified antibody, multiple modes of tumor cell killing must be engaged: immune effector function (ADCC, ADCP, or CDC) and growth inhibition mechanisms (apoptosis or cell cycle arrest).…”

Section: Discussionmentioning

confidence: 99%

“…CD19 has been a focus of immunotherapy development for over 20 years, and several CD19-specific antibodies have been evaluated for the treatment of B-lineage malignancies in vitro, in mouse models, and in clinical trials. These have included unmodified anti-CD19 antibodies (8,9), antibody-drug conjugates (10)(11)(12), and bispecific antibodies targeting CD19 and CD3 (13) or CD16 (14) to engage cytotoxic lymphocyte effector functions. Although early clinical studies with murine unconjugated CD19 antibodies showed safety and responses in individual patients, these responses were not durable (15).…”

Section: Introductionmentioning

confidence: 99%

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PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

et al. 2008

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CD19 is a pan B-cell surface receptor expressed from pro-B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non-Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fc; receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibodydependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fc; receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19 + hematologic malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

et al. 2008

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“…In an early attempt to improve ADCC in the context of monoclonal antibody therapy, Vlasveld and colleagues treated 7 patients with indolent B-cell lymphoma with a combination of a murine anti-CD19 antibody and continuous infusion low-dose IL-2, a lymphokine that enhances ADCC in vitro. 30 Lymphocytes from involved lymph nodes showed enhanced ADCC, which provided proof-of-principle.…”

Section: Enhancing Adccmentioning

confidence: 99%

Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy

Friedberg¹

2005

Hematology

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Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

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“…[5][6][7] With the exception of multiple myeloma, 8 CD19 is expressed in nearly all non-Hodgkin lymphomas and many leukemias. 9,10 Several anti-CD19 antibodies have been evaluated in the clinic for the treatment of such diseases, including unconjugated antibodies, 11,12 antibody-drug conjugates, 13,14 and bispecific antibodies targeting CD19 and CD3. 15,16 Despite the attractiveness of CD19 as an immunotherapeutic target for the treatment of B-cell malignancies, the results with patients have been mixed.…”

Section: Introductionmentioning

confidence: 99%

The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates

Zalevsky

Leung

Karki

et al. 2009

Blood

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CD19, a B cell-restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fc␥ receptor (Fc␥R) binding affinity, leading to improved Fc␥R-dependent effector cell functions and antitumor activity in murine xenografts compared with the non-Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing Fc␥R binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans. IntroductionCD19 is a B cell-restricted signal-transducing cell-surface receptor present on most B cells from the earliest stages of pre-B-cell development until terminal differentiation into plasma cells. 1,2 A critical role for CD19 in B-cell development and activation has been established using CD19-deficient mice. Such mice fail to develop a proper immune response after antigen challenge, exhibit decreased B-cell numbers in the periphery and in lymphoid tissues, lack germinal center (GC) formation, and have decreased serum immunoglobulin (Ig) levels. 1,3,4 Furthermore, anti-CD19 antibodies effectively deplete peripheral B cells in transgenic mice expressing human CD19 and block malignant B-cell growth in murine xenografts. [5][6][7] With the exception of multiple myeloma, 8 CD19 is expressed in nearly all non-Hodgkin lymphomas and many leukemias. 9,10 Several anti-CD19 antibodies have been evaluated in the clinic for the treatment of such diseases, including unconjugated antibodies, 11,12 antibody-drug conjugates, 13,14 and bispecific antibodies targeting CD19 and CD3. 15,16 Despite the attractiveness of CD19 as an immunotherapeutic target for the treatment of B-cell malignancies, the results with patients have been mixed. Thus, the challenge remains to optimize anti-CD19 antibodies to achieve improved clinical outcome.The potency of immunotherapeutics depends on multiple mechanisms of action, including those mediated by effector cells expressing Fc␥ receptors (Fc␥Rs). 17 Fc␥Rs in turn have activating or inhibitory functional roles and differ in their distribution among effector cells. Monocytes, macrophages, and neutrophils express both activating and inhibitor...

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Treatment of low-grade non-Hodgkin's lymphoma with continuous infusion of low-dose recombinant interleukin-2 in combination with the B-cell-specific monoclonal antibody CLB-CD19

Cited by 20 publications

References 44 publications

PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy

The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates

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