A Human ICAM-1 Antibody Isolated by a Function-First Approach Has Potent Macrophage-Dependent Antimyeloma Activity In Vivo

Veitonmäki, Niina; Hansson, Markus; Zhan, Fenghuang; Sundberg, Annika; Löfstedt, Tobias; Ljungars, Anne; Li, Zhanchun; Martinsson-Niskanen, Titti; Zeng, Ming; Yang, Ye; Danielsson, Lena; Kovacek, Mathilda; Lundqvist, Andrea; Mårtensson, Linda; Teige, Ingrid; Tricot, Guido; Frendéus, Björn

doi:10.1016/j.ccr.2013.02.026

Cited by 68 publications

(71 citation statements)

References 43 publications

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“…The potential benefit of targeting multiple myeloma tumor cells by specific mAbs alone or in combination with other antimultiple myeloma agents has also been demonstrated by other recent experimental and clinical studies (4,(20)(21)(22)(23)(24)(25)(26). For instance, bortezomib was described to synergistically enhance the lysis of ADCC mediated by the CS1 mAb elotuzumab in vitro (27).…”

Section: Discussionmentioning

confidence: 84%

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Nijhof

Groen

Noort

et al. 2015

Clinical Cancer Research

136

115

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Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide-and bortezomib-refractory patients.Experimental Design: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide-and bortezomib-refractory multiple myeloma patients.Results: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide-and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumabmediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide-and bortezomib-refractory patient.Conclusions: Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide-and bortezomib-refractory patients.

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Section: Discussionmentioning

confidence: 84%

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Nijhof

Groen

Noort

et al. 2015

Clinical Cancer Research

136

115

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“…10.1 (anti-FcgR1) was a gift from Nancy Hogg (London Research Institute, Cancer Research UK, London, UK); E05 (anti-FcgRIIa) and 6G11 (anti-FcgRIIb) with Fc regions mutated to eliminate FcgR binding were produced by BioInvent International AB (Malmo, Sweden) by using phage display technology 11 TGN1412 was produced by using published sequences (US patent number US7585960). Variable regions were subcloned into expression vectors (pEE6.4 heavy chain and pEE12.4 light chain; Lonza) containing constant regions of human IgG4.…”

Section: Antibodiesmentioning

confidence: 99%

Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

Hussain

Hargreaves

Roghanian

et al. 2015

Blood

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Key Points• TGN1412-induced T-cell activation following highdensity preculture of PBMCs is a consequence of FcgRIIb upregulation on monocytes.• In vivo, cytokine release syndrome may be due to the close association of FcgRIIbbearing cells with T cells in lymphoid tissues.The anti-CD28 superagonist antibody TGN1412 caused life-threatening cytokine release syndrome (CRS) in healthy volunteers, which had not been predicted by preclinical testing. T cells in fresh peripheral blood mononuclear cells (PBMCs) do not respond to soluble TGN1412 but do respond following high-density (HD) preculture. We show for the first time that this response is dependent on crystallizable fragment gamma receptor IIb (FcgRIIb) expression on monocytes. This was unexpected because, unlike B cells, circulating monocytes express little or no FcgRIIb. However, FcgRIIb expression is logarithmically increased on monocytes during HD preculture, and this upregulation is necessary and sufficient to explain TGN1412 potency after HD preculture. B-cell FcgRIIb expression is unchanged by HD preculture, but B cells can support TGN1412-mediated T-cell proliferation when added at a frequency higher than that in PBMCs. Although lowdensity (LD) precultured PBMCs do not respond to TGN1412, T cells from LD preculture are fully responsive when cocultured with FcgRIIb-expressing monocytes from HD preculture, which shows that they are fully able to respond to TGN1412-mediated activation. Our novel findings demonstrate that cross-linking by FcgRIIb is critical for the superagonist activity of TGN1412 after HD preculture, and this may contribute to CRS in humans because of the close association of FcgRIIb-bearing cells with T cells in lymphoid tissues. (Blood. 2015;125(1):102-110)

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“…BI-505 binds to intercellular adhesion molecule-1 (ICAM-1), suggesting a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope is strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients (5). BI-505 has potent macrophage-dependent anti-myeloma activity.…”

Section: Introductionmentioning

confidence: 99%

“…BI-505 has potent macrophage-dependent anti-myeloma activity. It has been shown to enhance survival in advanced disseminated murine models of myeloma compared with currently used treatments, and to inhibit primary myeloma cell growth and bone damage in an SCID-hu model when used in combination with lenalidomide and bortezomib (5).…”

Section: Introductionmentioning

confidence: 99%

“…BI-505 is a fully human high-affinity IgG1 antibody, which was isolated from a highly diverse human phage-antibody library based on its functional ability to induce programmed cell death of tumor cells (5). BI-505 binds to intercellular adhesion molecule-1 (ICAM-1), suggesting a previously unrecognized role for this receptor as a therapeutic target in cancer.…”

Section: Introductionmentioning

confidence: 99%

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A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

Hansson

Gimsing

Badros

et al. 2015

Clinical Cancer Research

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Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients.Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses.Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505 0 s half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months.Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206).

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A Human ICAM-1 Antibody Isolated by a Function-First Approach Has Potent Macrophage-Dependent Antimyeloma Activity In Vivo

Cited by 68 publications

References 43 publications

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Upregulation of FcγRIIb on monocytes is necessary to promote the superagonist activity of TGN1412

A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

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