Abstract Antibody Drug Conjugates (ADCs), such as trastuzumab deruxtecan, achieve complete responses 20% and duration of response 30 months in patients with metastatic Her2+ breast cancer1. However, other mono/bi-specific ADCs have not achieved similar clinical benefit, likely due to the 10-100x higher expression levels of Her2 vs other ADC targets, as well as known heterogeneity of target expression, down-regulation of targets in response to treatment and in some cases, competition from soluble target release. To address these fundamental limitations, we developed a novel class of engineered multifunctional multivalent multispecific therapeutics (SynthbodyTM) that enable targeting of combinatorial “synthetic” cancer targets incorporating 6-12 tumor antigen binding domains. This replicates Her2-like high expression and specificity for ADC therapeutics in most tumors without high levels of expression of a single specific tumor antigen. We engineered an initial human multiple myeloma targeting SynthbodyTM, referred to as SDF-061390E, that includes affinity-tuned binders for BCMA, GPRC5D and CD38. SDF-061390E (and SDF-061390E-MMAF) demonstrates 30x greater internalization and 80x greater potency when compared, respectively, with the BCMA-targeting antibody Belantamab and Belantamab mafodotin in human myeloma cells. Enhanced internalization and potency are similarly observed when compared against matched mono/bi-specific controls. Additionally, SDF-061390E can bind human myeloma cell lines with both high and low expression of each of the three targets and effectively eliminate low-BCMA expressing cancer cells in ADC killing assays. Further, SDF-061390E can evade impact of soluble BCMA at clinically relevant and higher concentrations, in contrast to belantamab. Similar results are also observed with a NHL targeting SynthbodyTM, supporting the broad applicability. Due to biophysical characteristics that can be controlled in the design of Synthbody™ constructs, we generate emergent properties, including conditional activity determined by the geometry and biophysical relationships between the cancer cell antigens, epitopes, and the SynthbodyTM. This architecture enables the Synthbody™ ADCs to include AND BETTER logic-gated control, layered with AND safety gates and MULTIPLIER functions, yielding synergistic multifunctional activity absent from ADCs. Optimized Synthbody™ constructs show excellent production in CHO cells, developability and IgG-like PK in vivo. The novel Synthbody™ platform demonstrates broad utility as ADC and biologic therapeutics, with capabilities for coordinated targeting, advanced logic-gated control and multifunctional action that may complement or ultimately replace current IgG-based biologics. Citation Format: Ramesh Baliga, Keyu Li, Kristene Mai, Harrison Horwitz, Zhefu Dai, Sachi Ahmed, Vidhya Rao, Poonam Yakkundi, Maya Leabman, Daniel S. Chen. Synthbody™- A novel multivalent multispecific antibody drug conjugate platform demonstrates combinatorial logic-gated “synthetic” targeting of cancer antigens with log order enhanced internalization and potency abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1321.
Baliga et al. (Fri,) studied this question.