CD200 Antagonists Compared Against CLL

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J Immunol. 2008 Jan 15;180(2):699-705.

Blockade of CD200 in the Presence or Absence of Antibody Effector

Function: Implications for Anti-CD200 Therapy.

Kretz-Rommel A, Qin F, Dakappagari N, Cofiell R, Faas SJ, Bowdish KS.

ion Antibody Technologies, San Diego, CA 92121.

CD200 is an immunosuppressive molecule overexpressed in multiple

hematologic malignancies such as B cell chronic lymphocytic leukemia,

multiple myeloma, and acute myeloid leukemia.

We previously demonstrated that up-regulation of CD200 on tumor cells

suppresses antitumor immune responses and that antagonistic anti-human

CD200 mAbs enabled human PBMC-mediated tumor growth inhibition in

xenograft NOD/SCID human (hu)-mouse models. Ab variants with effector

function (IgG1 constant region (G1)) or without effector function

(IgG2/G4 fusion constant region (G2G4)) exhibited high antitumor

activity in a human tumor xenograft model in which CD200 was expressed.

In this report, we seek to select the best candidate to move forward

into the clinic and begin to decipher the mechanisms of tumor cell

killing by comparing anti-CD200-G1 vs anti-CD200-G2G4 in two related

animal models.

In a CD200-expressing xenograft NOD/SCID hu-mouse model where CD200

ligand/receptor interactions are already established before initiating

treatment, we find that anti-CD200-G1 is a less effective Ab compared

with anti-CD200-G2G4. Separately, in a model that evaluates the effect

of the Abs on the immune cell component of the xenograft NOD/SCID

hu-mouse model distinctly from the effects of binding to CD200 on

tumor cells, we find that the administration of anti-CD200-G1 Abs

completely abolished human PBMC-mediated tumor growth inhibition.

Along with supporting in vitro studies, our data indicate that

anti-CD200-G1 Abs efficiently mediate Ab-dependent cellular

cytotoxicity of activated T cells, critical cells involved in

immune-mediated killing. These studies suggest important implications

regarding the selection of the constant region in anti-CD200

immunotherapy of cancer patients.

PMID: 18178807 [PubMed - in process]