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Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma

Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma
Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma
CD64 (Fc?RI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colony-stimulating factor (G-CSF)–activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against immunoglobulin-idiotype (Id), major histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effectors. In vitro cytotoxicity assays and in vivo tumor tracking showed that, provided effectors were activated with G-CSF, all 3 derivatives destroyed and cleared lymphoma cells, with (huCD64?×?MHC II) proving by far the most cytotoxic in vitro. However, though all derivatives delivered some survival advantage, only the [huCD64?×?Id] BsAb provided long-term protection to tumor-bearing animals. These results demonstrate that CD64-recruited cytotoxic effectors operate in vivo but that the (huCD64?×?Id) conferred an additional anti-tumor function essential for long-term protection. T-cell depletion studies demonstrated that this extra therapeutic activity with [huCD64?×?Id] was totally dependent on CD4 and CD8 T cells and that mice, once “cured” with BsAb, were resistant to tumor rechallenge. These findings indicate that CD64 is an effective trigger molecule for delivering cytokine-activated PMN against tumor in vivo and that, provided tumor targets are selected appropriately, CD64-based BsAb can establish long-term T-cell immunity.

0006-4971
3544-3552
Honeychurch, Jamie
4ecce821-9d37-4c35-bcb3-871ff832a3d2
Tutt, Alison L.
46ce577b-aea1-412d-84ea-fc4dab794469
Heijnen, Ingmar A.F.M.
297d45d8-7c46-4dfb-9423-c86c838dbac2
van de Winkel, Jan G.J.
003d19da-52d5-4e0b-84ef-7a1b42b7ae6d
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Honeychurch, Jamie
4ecce821-9d37-4c35-bcb3-871ff832a3d2
Tutt, Alison L.
46ce577b-aea1-412d-84ea-fc4dab794469
Heijnen, Ingmar A.F.M.
297d45d8-7c46-4dfb-9423-c86c838dbac2
van de Winkel, Jan G.J.
003d19da-52d5-4e0b-84ef-7a1b42b7ae6d
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded

Honeychurch, Jamie, Tutt, Alison L., Heijnen, Ingmar A.F.M., van de Winkel, Jan G.J. and Glennie, Martin J. (2000) Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma. Blood, 96 (10), 3544-3552. (PMID:11071653)

Record type: Article

Abstract

CD64 (Fc?RI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colony-stimulating factor (G-CSF)–activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against immunoglobulin-idiotype (Id), major histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effectors. In vitro cytotoxicity assays and in vivo tumor tracking showed that, provided effectors were activated with G-CSF, all 3 derivatives destroyed and cleared lymphoma cells, with (huCD64?×?MHC II) proving by far the most cytotoxic in vitro. However, though all derivatives delivered some survival advantage, only the [huCD64?×?Id] BsAb provided long-term protection to tumor-bearing animals. These results demonstrate that CD64-recruited cytotoxic effectors operate in vivo but that the (huCD64?×?Id) conferred an additional anti-tumor function essential for long-term protection. T-cell depletion studies demonstrated that this extra therapeutic activity with [huCD64?×?Id] was totally dependent on CD4 and CD8 T cells and that mice, once “cured” with BsAb, were resistant to tumor rechallenge. These findings indicate that CD64 is an effective trigger molecule for delivering cytokine-activated PMN against tumor in vivo and that, provided tumor targets are selected appropriately, CD64-based BsAb can establish long-term T-cell immunity.

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Published date: 15 November 2000

Identifiers

Local EPrints ID: 179907
URI: http://eprints.soton.ac.uk/id/eprint/179907
ISSN: 0006-4971
PURE UUID: 63532f3a-eb05-48b6-92bb-d6ce276f5bf4

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Date deposited: 08 Apr 2011 13:43
Last modified: 22 Jul 2022 17:37

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Contributors

Author: Jamie Honeychurch
Author: Alison L. Tutt
Author: Ingmar A.F.M. Heijnen
Author: Jan G.J. van de Winkel

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