Classic ADCs consist of monoclonal antibodies (mAbs) linked to drugs or toxins. They selectively deliver toxic moieties to tumor cells. As such, they greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the therapeutic efficacy and safety of ADCs are dependent on linker stability and payload toxicity. Limited payload number on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents: currently four types of payloads with IC50 from 0.1 nM to pM are used including auristatin, calicheamicin, maytansine and PBD, which are too toxic to be used alone. Even very low off-target binding of these ADCs may induce severe side-effects.
Given these challenges, an alternative approach is needed to enhance drug delivery while maintaining safety. Polymer-enhanced antibody drug conjugates (pADCs) represent a promising next-generation therapeutic platform that integrates the specificity of mAbs with the controlled drug delivery benefits of polymer-based carriers. Unlike conventional ADCs that use small-molecule linkers with a limited DAR, pADCs utilize semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates, which enables a significant increase in the DAR, reaching up to 40, far exceeding that of conventional ADCs. The hydrophilicity and excellent solubility of the HPMA copolymer backbone enhance stability and pharmacokinetics of pADCs, preventing aggregation issues commonly seen in highly loaded ADCs while maintaining efficient drug delivery (Fig. 4). By achieving a higher DAR without compromising solubility or increasing systemic toxicity, HPMA-based pADCs offer a safer and more effective drug delivery approach compared to conventional ADCs (Fig. 5) [1-3].
Figure 5. Mechanism of action and efficacy. (A) early-stage and (B) advanced-stage disease models. (C,D) Kaplan-Meier survival analysis: Percent survival of mice treated with U6244-051, control ADC, α-PD-L1, or saline control in (C) early-stage (n = 4–5) and (D) advanced-stage (n = 7) disease models. U6244-051 significantly prolonged survival compared to other treatments in both models. (E,F) Tumor progression monitored by IVIS imaging: Representative bioluminescence images showing weekly tumor growth in (E) early-stage and (F) advanced-stage disease models. U6244-051 treatment led to a marked reduction in tumor burden, consistent with extended survival.
References:
[1] A New Construct of Antibody-Drug Conjugates for Treatment of Non-Hodgkin’s Lymphoma. L. Zhang, Y. Fang, J. Kopeček, J. Yang, Eur. J. Pharm. Sci. 103, 36-46 (2017) [doi]
[2] PD-L1 targeted antibody-polymer-Epirubicin conjugate prolongs survival in a preclinical murine model of advanced ovarian cancer. J. Li, H.A. Al Faruque, S. Li, M. Sima, D. Sborov, S. Hu-Lieskovan, T. Werner, J. Kopeček, J. Yang. J. Controlled Release 382, 113682 (2025) [doi]
[3] CD38-Targeted Antibody-Polymer Drug Conjugates for Enhanced Treatment of Multiple Myeloma. J. Li, S. Li, H. Al Faruque, J. Kopeček, D.W. Sborov, J. Yang, Biomaterials, in revision.