Pharmacokinetics of radiolabeled dimeric sdAbs constructs targeting human CD20

Area of Science:

• Biochemistry
• Radiopharmaceutical Science
• Oncology

Background:

• Single-domain antibody fragments (sdAbs) are small, functional antigen-binding fragments from camelid antibodies.
• Radiolabeled monomeric sdAbs offer fast, specific tumor targeting for cancer imaging and therapy, achieving high tumor-to-background ratios.
• However, their absolute tumor uptake may be insufficient for effective cancer treatment.

Purpose of the Study:

• To evaluate the pharmacokinetics and tumor targeting of seven constructs derived from a CD20-targeting sdAb (αCD20).
• To compare monomeric, dimeric, and albumin-fused αCD20 constructs for their potential in cancer radioimmunotherapy.

Main Methods:

• Constructs were radiolabeled with 111In (imaging) and 177Lu (therapy) using CHX-A"-DTPA.
• In vitro and in vivo evaluations were performed in mice, assessing tumor uptake, blood clearance, and tumor-to-blood ratios.

Main Results:

• Monomeric 177Lu-DTPA-αCD20 showed rapid blood clearance and high tumor-to-blood ratios (>100) within 24 hours.
• Dimeric αCD20-αCD20 did not show superior in vivo internalization compared to monomeric form, despite in vitro promise.
• αCD20-αAlb constructs exhibited slower blood clearance and significantly higher absolute tumor uptake, but lower tumor-to-blood ratios.

Conclusions:

• Increased size (dimeric αCD20-αCD20) or albumin fusion (αCD20-αAlb) of sdAbs can counterbalance improved tumor targeting capacity.
• Pharmacokinetic optimization is crucial for enhancing the therapeutic efficacy of CD20-targeting sdAbs in cancer treatment.