[64Cu]Cu-Labeled αCD11b Diabody as a Novel PET Tracer for the Detection of Immunosuppression in Glioblastoma

TL;DR

A new PET tracer is developed to detect immunosuppressive cells in glioblastoma, potentially improving immunotherapy effectiveness.

Contribution

A novel [64Cu]Cu-labeled αCD11b diabody is introduced for PET imaging of CD11b-positive tumor-associated myeloid cells in glioblastoma.

Findings

The tracer achieved optimal tumor uptake at 4 hours post-administration with a %ID/g of 1.06 in tumors.

Molar activity of 2.12 MBq/nmol provided optimal tracer uptake due to modulation by CD11b antigen sink.

The tracer effectively visualized TAMCs in a syngeneic mouse model of glioblastoma.

Abstract

Glioblastoma multiforme
(GBM) is one of the deadliest
types of
cancer that occurs in people of all ages; 15 months is the average
survival time. While treatments for GBM are mostly unsuccessful, immunotherapy
has the potential to be an effective strategy for glioblastoma. However,
the immunosuppressive influence of tumor-associated myeloid cells
(TAMCs) results in poor responses to immunotherapy. As TAMCs are CD11b-positive,
the potential of a radiolabeled αCD11b diabody was investigated
to assess immunosuppression mediated by TAMCs in an immunocompetent
mouse model of glioblastoma. An αCD11b diabody (Db) was constructed
with the VH and VL sequences of an αCD11b IgG that resulted
in thermal stability and high affinity. αCD11b Db was conjugated
with a cross-bridged chelator, CB-TE1K1P, through click chemistry.
The resulting conjugate was radiolabeled with 64Cu and
investigated in vitro and in a model of glioblastoma.
[64Cu]­Cu-αCD11b Db visualized TAMCs in a syngeneic
mouse glioblastoma, achieving optimal uptake within 4 h post administration
with a %ID/g of 1.06 and 0.18 for tumor and healthy brain tissue.
In correlating molar activity (8.51, 4.26, 2.12, and 1.06 MBq/nmol)
with uptake (%ID/g of 0.162, 0.825, 1.06, and 0.445, respectively),
we demonstrated that 2.12 MBq/nmol gave optimal uptake, since tracer
pharmacokinetics was modulated by αCD11b Db occupation of the
CD11b antigen sink. In conclusion, [64Cu]­Cu-αCD11b
Db is a high-affinity and stable diabody, which can quantify CD11b-positive
TAMCs in the tumor microenvironment, particularly when the molar activity
of the administered [64Cu]­Cu-αCD11b Db is optimized
for managing the CD11b antigen sink in the spleen, liver, and bone
marrow.

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