MYTX-011 is an investigational, pH-sensitive, vcMMAE ADC. It has been designed to benefit a broader population of patients whose tumors express lower/moderate levels of cMET. MYTX-011 drives increased internalization and cytotoxicity and shows robust activity in xenograft models across a range of levels of cMET expression. Early clinical data demonstrate a differentiated profile: extended PK, low free MMAE release, and low incidence of side effects commonly associated with vcMMAE ADCs.

Chain exchange technologies can be used to generate binder-format matrices of bispecific antibodies. Similar to the optimization of bsAbs, chain-exchange can also generate ADC-matrices by combining different binders, formats, attachment-positions and payloads. As an example, a Her2-ADC matrix with payloads attached in different formats, positions and stoichiometries reveals that ‘format-defines-function’ applies not only to bsAbs but also to ADCs.

Payload resistance is a critical concern for ADCs. Combinations may be beneficial but therapeutic windows are limited. Hummingbird Bioscience's dual-payload ADC platform is a targeted, single-agent approach designed to overcome resistance and maximize therapeutic window. HMBD-802, an anti-HER2 dual-payload ADC shows robust efficacy in trastuzumab deruxtecan resistant models and good tolerability.

99% of a dose of an ADC is eliminated by normal tissues, causing efficacy limiting toxicities. Shasqi has developed an approach to overcome this problem by separating tumor binding from the payload and enabling selective payload activation at the tumor using click chemistry. This approach maximizes efficacy and therapeutic index by reducing toxicities.

Radiolabeled antibodies are essential in cancer theranostics and radio-immunotherapy (RIT) due to their high specificity for cancer antigens. While promising, RIT faces challenges including long half-life leading to prolonged radioactivity exposure. This presentation explores strategies to improve RIT efficacy and safety, including combination therapies with drugs that modulate radiation response or interact with the immune system, as well as antibody modifications, and optimized administration techniques.

Immunostimulatory antibody conjugates (ISACs) often rely on Fcγ receptor (FcγR) interactions to activate immune cells and drive tumor regression. However, these interactions may also contribute to immune-related side effects. To address this, we are developing deglycosylated ISACs that bypass FcγR binding. Tested in HER2+ breast and Trop2+ pancreatic cancer models, these ISACs maintained potent tumor-specific immune activation while potentially minimizing off-target effects. Ongoing studies are exploring the link between immunogenicity and FcγR binding.