Anti-Idiotype × Anti-CD44 Bispecific Antibodies Inhibit Invasion of Lymphoid Organs by B Cell Lymphoma

Avin, Esther; Haimovich, Joseph; Hollander, Nurit

doi:10.4049/jimmunol.173.7.4736

Cited by 19 publications

(15 citation statements)

References 50 publications

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“…Nonetheless, due to abundant CD44 expression in hematopoietic cells including HSC, anti-panCD44 has also been reported to be burdened by side effects [5,44]. Therefore, we explored for CD44v10 transfected EL4, EL4 not expressing other CD44 variants (M.Zöller unpublished), whether side effects can be circumvented or mitigated by antibodies specific for splice variants that expression is far more restricted [45].…”

Section: Discussionmentioning

confidence: 99%

CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells

Erb¹,

Megaptche²,

Gu³

et al. 2014

J Hematol Oncol

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BackgroundA blockade of CD44 is considered a therapeutic option for the elimination of leukemia initiating cells. However, anti-panCD44 can interfere with hematopoiesis. Therefore we explored, whether a CD44 variant isoform (CD44v)-specific antibody can inhibit leukemia growth without attacking hematopoiesis. As a model we used CD44v10 transfected EL4 thymoma cells (EL4-v10).MethodsThe therapeutic efficacy of anti-panCD44 and anti-CD44v10 was evaluated after intravenous application of EL4/EL4-v10. Ex vivo and in vitro studies evaluated the impact of anti-panCD44 and anti-CD44v10 as well as of EL4 and EL4-v10 on hematopoietic stem cells (HSC) in cocultures with bone marrow stroma cells with a focus on adhesion, migration, cell cycle progression and apoptosis resistance.ResultsIntravenously injected EL4-v10 grow in bone marrow and spleen. Anti-panCD44 and, more pronounced anti-CD44v10 prolong the survival time. The higher efficacy of anti-CD44v10 compared to anti-panCD44 does not rely on stronger antibody-dependent cellular cytotoxicity or on promoting EL4-v10 apoptosis. Instead, EL4 compete with HSC niche embedding. This has consequences on quiescence and apoptosis-protecting signals provided by the stroma. Anti-panCD44, too, more efficiently affected embedding of HSC than of EL4 in the bone marrow stroma. EL4-v10, by catching osteopontin, migrated on bone marrow stroma and did not or weakly interfere with HSC adhesion. Anti-CD44v10, too, did not affect the HSC – bone marrow stroma crosstalk.ConclusionThe therapeutic effect of anti-panCD44 and anti-CD44v10 is based on stimulation of antibody-dependent cellular cytotoxicity. The superiority of anti-CD44v10 is partly due to blocking CD44v10-stimulated osteopontin expression that could drive HSC out of the niche. However, the main reason for the superiority of anti-CD44v10 relies on neither EL4-v10 nor anti-CD44v10 severely interfering with HSC – stroma cell interactions that, on the other hand, are affected by EL4 and anti-panCD44. Anti-panCD44 disturbing HSC embedding in the osteogenic niche weakens its therapeutic effect towards EL4. Thus, as far as leukemic cells express CD44v isoforms, the therapeutic use of anti-panCD44 should be avoided in favor of CD44v-specific antibodies.

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Section: Discussionmentioning

confidence: 99%

CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells

Erb¹,

Megaptche²,

Gu³

et al. 2014

J Hematol Oncol

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“…26,27 The fact that untreated tumor-bearing mice succumbed to lymphoma in 20 days and that combination treatment with chemotherapy, anti-CD20 antibodies, and intratumoral injection of DCs led to long-term survival indirectly indicated that local intratumoral DC injection had a systemic antitumor effect. To further demonstrate that the combined treatment has a synergistic effect on a systemic disease rather than on a local tumor only, we determined whether disease was already spread at the onset of treatment.…”

Section: C-13-cd20 Tumors Are Already Spread At the Onset Of Combinmentioning

confidence: 98%

Synergistic Effect of Dendritic Cell Vaccination and Anti-CD20 Antibody Treatment in the Therapy of Murine Lymphoma

Gadri

Kukulansky

Bar-Or

et al. 2009

Journal of Immunotherapy

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Indolent B-cell lymphomas are characterized by repeated remissions and relapses with most patients eventually dying of the disease. Although combination treatments with chemotherapy and the anti-CD20 antibody rituximab improved duration of remissions and overall survival, the disease is essentially incurable. Thus, novel therapeutic approaches are needed. One such approach is active immunization with dendritic cells (DCs). Given that rituximab depletes patients of normal B cells, optimal vaccination strategies for rituximab-treated patients require induction of effector T cells. We have previously demonstrated in a murine model that idiotype (Id)-keyhole limpet hemocyanin-pulsed DCs induced Id-reactive CD8 T cells and protection against tumor challenge in the absence of anti-Id antibodies. On the basis of these results, we investigated vaccination in a therapeutic model, in which mice carrying advanced tumors of the highly aggressive 38C-13 lymphoma were treated with chemotherapy and anti-CD20 antibodies combined with a DC-based vaccine. As a rule, cytoreduction by cyclophosphamide was required in each regimen of combination treatment, and vaccination with tumor cell-loaded DCs was more effective than vaccination with Id-keyhole limpet hemocyanin-loaded DCs. We demonstrated that under conditions of large primary tumors that had already spread to lymph nodes, when anti-CD20 antibody treatment showed minimal effect and DC vaccination had no effect, synergism between anti-CD20 antibodies and DC vaccines resulted in significant long-term survival that did not involve active antitumor antibody production. Combination treatments including tumor cell-loaded DC vaccines may therefore provide a strategy for enhancing the potency of therapy in rituximab-treated patients.

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“…As reported by Avin et al (65) for the therapy of a B cell lymphoma, a bispecific Ab targeting CD44 and a B leukemia marker circumvents side effects. It more efficiently disrupts the communication between the leukemia cell and the host and still stimulates a nonadaptive immune response.…”

Section: Cd44 Cd49d and Leukemia Cell Proliferation And Apoptosis Rmentioning

confidence: 99%

Cooperativity of CD44 and CD49d in Leukemia Cell Homing, Migration, and Survival Offers a Means for Therapeutic Attack

Singh

Erb

Zöller

2013

The Journal of Immunology

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A CD44 blockade drives leukemic cells into differentiation and apoptosis by dislodging from the osteogenic niche. Because anti-CD49d also supports hematopoietic stem cell mobilization, we sought to determine the therapeutic efficacy of a joint CD49d/CD44 blockade. To unravel the underlying mechanism, the CD49d− EL4 lymphoma was transfected with CD49d or point-mutated CD49d, prohibiting phosphorylation and FAK binding; additionally, a CD44− Jurkat subline was transfected with murine CD44, CD44 with a point mutation in the ezrin binding site, or with cytoplasmic tail–truncated CD44. Parental and transfected EL4 and Jurkat cells were evaluated for adhesion, migration, and apoptosis susceptibility in vitro and in vivo. Ligand-binding and Ab-blocking studies revealed CD44–CD49d cooperation in vitro and in vivo in adhesion, migration, and apoptosis resistance. The cooperation depends on ligand-induced proximity such that both CD44 and CD49d get access to src, FAK, and paxillin and via lck to the MAPK pathway, with the latter also supporting antiapoptotic molecule liberation. Accordingly, synergisms were only seen in leukemia cells expressing wild-type CD44 and CD49d. Anti-CD44 together with anti-CD49d efficiently dislodged EL4-CD49d/Jurkat-CD44 in bone marrow and spleen. Dislodging was accompanied by increased apoptosis susceptibility that strengthened low-dose chemotherapy, the combined treatment most strongly interfering with metastatic settlement and being partly curative. Ab treatment also promoted NK and Ab-dependent cellular cytotoxicity activation, which affected leukemia cells independent of CD44/CD49d tail mutations. Thus, mostly owing to a blockade of joint signaling, anti-CD44 and anti-CD49d hamper leukemic cell settlement and break apoptosis resistance, which strongly supports low-dose chemotherapy.

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Anti-Idiotype × Anti-CD44 Bispecific Antibodies Inhibit Invasion of Lymphoid Organs by B Cell Lymphoma

Cited by 19 publications

References 50 publications

CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells

CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells

Synergistic Effect of Dendritic Cell Vaccination and Anti-CD20 Antibody Treatment in the Therapy of Murine Lymphoma

Cooperativity of CD44 and CD49d in Leukemia Cell Homing, Migration, and Survival Offers a Means for Therapeutic Attack

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