Systemically-administered labeled antibodies in cancer patients prior to surgery has allowed us to successfully measure antibody concentration in normal and tumor tissues. The biggest impact of this strategy is the ability to localize the antibody within tissues at the cellular level. We hypothesize that near-infrared, fluorescently labeled antibodies can be leveraged to estimate the dose at which the antibody reaches maximal tumor saturation, most notably for antibody-drug conjugates.

Target-mediated drug disposition (TMDD) is a case in which binding of a drug to its pharmacological target influences the pharmacokinetics of the drug. This phenomenon represents a major distribution/elimination process for many antibody-based constructs. This talk will review the basic tenets of TMDD, highlight how computational modeling of TMDD is being used to guide the design and development of antibodies and antibody-drug conjugates, and potential clinical implications of TMDD.

ADCC provides a model for uncovering immune resistance mechanisms. We have continuously exposed different cancer cell lines to KIR-deficient NK92-CD16V effector cells and ADCC-promoting monoclonal antibodies. We show that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity. These findings have implications for resistance to diverse forms of cancer immunotherapy.

Over the past several years, we have developed an antibody-based platform approach for parenterally targeted radiotherapy with a goal of cures without histologic evidence of radiotoxicity in laboratory models of highly radioresistant solid tumors. Using a radiohapten capture system developed in collaboration with the Wittrup Laboratory of MIT, we have demonstrated proof of principle with beta- and alpha-emitting radionuclides in 3 solid tumors (antigen targets): neuroblastoma (GD2), breast cancer (Her 2), and colon cancer (A33).

BCMA has become the leading new target for multiple myeloma with several BCMA-targeting agents in clinical development. GSK’s belantamab mafodotin is an antibody-drug conjugate which has recently completed a pivotal study in 4th line of treatment in patients with multiple myeloma. This presentation provides an update on the pivotal data and overall clinical program of belantamab mafodotin.

TRPH-222 is a CD22-directed ADC, constructed via a novel, site-specific (SMARTag™) conjugation approach, resulting in highly controlled and reproducible drug loading. TRPH-222 is being studied in relapsed and/or refractory B cell lymphoma patients in a phase 1 clinical trial (NCT03682796); currently, the trial is enrolling patients in the dose-escalation phase, with promising tolerability, PK, and PD, as well as early signs of clinical efficacy in this single agent study.

HER2-targeted therapies have transformed the treatment of patients, but there remains a need for well tolerated and effective treatments across a range of HER2 expression levels. ZW49 is a bispecific antibody-drug conjugate that combines the ZymeLink™ linker-payload with the unique mechanisms of action of a biparatopic, anti-HER2 Azymetric antibody. ZW49 has the potential to address the unmet medical need across a range of HER2-expressing cancers.

MMAE-based ADCs have demonstrated the potential to change the natural history of multiple cancers. MMAE, the cytotoxic payload, has been shown to induce immunogenic cell death. Combining MMAE-based ADCs with immunotherapy has the promise of augmenting the benefit of each of these therapies.

If success is measured by regulatory approval, then 2019 and 2020 were successful years for antibody drug conjugates. With the approvals of enfortumab vedotin-ejfv, polatuzumab vedotin-piiq, fam-trastuzumab deruxtecan-nxki, and more recently sacituzumab govitecan-hziy by the Food and Drug Administration in the past 18 months exemplifies how the platform has evolved over the last 25 years. I will review the clinical lessons learned and opportunities to broaden the field.