Reducing Target Binding Affinity Improves The Therapeutic Index Of
Anti-MET Antibody Drug Conjugate In Tumor Bearing Animals
Abstract
• Background And Purpose: Many oncology ADCs have failed to demonstrate
efficacy in clinic because of dose-limiting toxicity. We developed an
approach that harnesses ADC affinity to broaden the therapeutic index
(TI). • Experimental Approach: Two anti-mesenchymal-epithelial
transition factor (MET) monoclonal antibodies (mAbs) with high affinity
(HAV) or low affinity (LAV) were studied. IVM studies were conducted in
rats to visualize and identify the cellular disposition of the mAbs
within the liver and kidney. A rat HT-29 xenograft model was used to
evaluate the in vivo anti-tumor efficacy of the two mAbs conjugated to
monomethyl auristatin E (MMAE). The pharmacokinetics (PK) and toxicity
profiles were also evaluated in rats. Single photon emission computed
tomography (SPECT/CT) studies revealed the ADC tissue biodistribution,
while mass spectroscopy measured free payload concentration in different
organs. • Key Results: The estimated TI for LAV-ADC was at least 3 times
greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of
anti-tumor activity, while the 111In-DTPA studies showed simlar amounts
of the ADCs in HT29 tumors. Although the LAV-ADC has slower blood
clearance, higher liver toxicity was observed with HAV-ADC. While the
SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher
accumulation and rapid clearance in normal tissues, the IVM studies
confirmed HAV mAb accumulates within hepatic sinusoidal endothelial
cells while the LAV mAb does not. • Conclusion And Implications:
Lowering the MET binding affinity provides a larger TI for MET-ADC.
Decreasing the affinity of the ADC reduces the TMDD to MET expressed in
normal tissues while maintaining uptake/delivery to the tumor.