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Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody

Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody
Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody
We evaluated the dose requirements for sustained in vivo activity of ofatumumab, a human anti-CD20 antibody under development for the treatment of B cell-mediated diseases. In a mouse xenograft model, a single dose, resulting in an initial plasma antibody concentration of 5 microg/ml, which was expected to result in full target saturation, effectively inhibited human B-cell tumour development. Tumour growth resumed when plasma concentrations dropped below levels that are expected to result in half-maximal saturation. Notably, tumour load significantly impacted antibody pharmacokinetics. In monkeys, initial depletion of circulating and tissue residing B cells required relatively high-dose levels. Re-population of B-cell compartments, however, only became detectable when ofatumumab levels dropped below 10 microg/ml. We conclude that, once saturation of CD20 throughout the body has been reached by high initial dosing, plasma concentrations that maintain target saturation on circulating cells (5-10 microg/ml) are probably sufficient for sustained biological activity. These observations may provide a rationale for establishing dosing schedules for maintenance immunotherapy following initial depletion of CD20 positive (tumour) cells.

antibody therapy, B cells, leukaemia, animal model
0007-1048
303-312
Bleeker, Wim K.
6a6a8012-91b2-4b02-b216-2356c6959544
Munk, Martin E.
fdb0bddf-0a68-45ac-9870-67506fee759a
Mackus, Wendy J.M.
6bfc99df-f20f-447c-96ff-f3ae0d4434c1
van den Brakel, Jeroen H.N.
0ae1235c-1848-40da-bdae-3b1fd251e02c
Pluyter, Marielle
38c0ab28-e4e8-40cd-803d-b4694eb6e7eb
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
van de Winkel, Jan G.J.
003d19da-52d5-4e0b-84ef-7a1b42b7ae6d
Parren, Paul W.H.L.
9065d0b7-6864-4840-a1ab-472c5abde41b
Bleeker, Wim K.
6a6a8012-91b2-4b02-b216-2356c6959544
Munk, Martin E.
fdb0bddf-0a68-45ac-9870-67506fee759a
Mackus, Wendy J.M.
6bfc99df-f20f-447c-96ff-f3ae0d4434c1
van den Brakel, Jeroen H.N.
0ae1235c-1848-40da-bdae-3b1fd251e02c
Pluyter, Marielle
38c0ab28-e4e8-40cd-803d-b4694eb6e7eb
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
van de Winkel, Jan G.J.
003d19da-52d5-4e0b-84ef-7a1b42b7ae6d
Parren, Paul W.H.L.
9065d0b7-6864-4840-a1ab-472c5abde41b

Bleeker, Wim K., Munk, Martin E., Mackus, Wendy J.M., van den Brakel, Jeroen H.N., Pluyter, Marielle, Glennie, Martin J., van de Winkel, Jan G.J. and Parren, Paul W.H.L. (2008) Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody. British Journal of Haematology, 140 (3), 303-312. (doi:10.1111/j.1365-2141.2007.06916.x).

Record type: Article

Abstract

We evaluated the dose requirements for sustained in vivo activity of ofatumumab, a human anti-CD20 antibody under development for the treatment of B cell-mediated diseases. In a mouse xenograft model, a single dose, resulting in an initial plasma antibody concentration of 5 microg/ml, which was expected to result in full target saturation, effectively inhibited human B-cell tumour development. Tumour growth resumed when plasma concentrations dropped below levels that are expected to result in half-maximal saturation. Notably, tumour load significantly impacted antibody pharmacokinetics. In monkeys, initial depletion of circulating and tissue residing B cells required relatively high-dose levels. Re-population of B-cell compartments, however, only became detectable when ofatumumab levels dropped below 10 microg/ml. We conclude that, once saturation of CD20 throughout the body has been reached by high initial dosing, plasma concentrations that maintain target saturation on circulating cells (5-10 microg/ml) are probably sufficient for sustained biological activity. These observations may provide a rationale for establishing dosing schedules for maintenance immunotherapy following initial depletion of CD20 positive (tumour) cells.

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Published date: February 2008
Keywords: antibody therapy, B cells, leukaemia, animal model

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Local EPrints ID: 153871
URI: https://eprints.soton.ac.uk/id/eprint/153871
ISSN: 0007-1048
PURE UUID: bcaba09c-9390-4206-a105-c1843d76a2f2

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Date deposited: 02 Jun 2010 15:29
Last modified: 16 Jul 2019 23:58

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Contributors

Author: Wim K. Bleeker
Author: Martin E. Munk
Author: Wendy J.M. Mackus
Author: Jeroen H.N. van den Brakel
Author: Marielle Pluyter
Author: Jan G.J. van de Winkel
Author: Paul W.H.L. Parren

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