Biparatopic antibodies: therapeutic applications and prospects.

Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.

MYTX-011: A pH-Dependent Anti-c-MET Antibody-Drug Conjugate Designed for Enhanced Payload Delivery to c-MET-Expressing Tumor Cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a c-mesenchymal-epithelial transition (MET)-targeting ADC (MYTX-011) can overcome the requirement for high c-MET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower c-MET levels. MYTX-011 drove fourfold higher net internalization than a non-pH-engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least threefold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high c-MET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other monomethyl auristatin E-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of patients with NSCLC with c-MET expression than other c-MET-targeting ADCs. A first-in-human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels. MYTX-011 drove four-fold higher net internalization than a non-pH engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least three-fold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high cMET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other MMAE-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of NSCLC patients with cMET expression than other cMET targeting ADCs. A first in human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).