Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate
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Abstract
Probody therapeutics (Pb-Txs) are conditionally activated antibody–drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody–drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic.
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CX-2029 is an ADC that links a protease-activatable antibody prodrug targeting TfR1 to cytotoxin monomethyl auristatin E (MMAE) using a cysteine protease-cleavable dipeptide as linker.
“CX-2029 is an ADC that linked a protease-activatable antibody prodrug targeting TfR1 to cytotoxin monomethyl auristatin E (MMAE) using a cysteine protease-cleavable dipeptide as linker.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [650]
CX-2029 is designed to be unmasked in the tumor microenvironment, resulting in tumor selectivity.
“It is designed to be unmasked in tumor microenvironment, resulting in tumor selectivity.650”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [650]
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- Authors
- Singh, S., Serwer, L., DuPage, A., Elkins, K., Chauhan, N., Ravn, M., Buchanan, F., Wang, L., Krimm, M., Wong, K., Sagert, J., Tipton, K., Moore, S. J., Huang, Y., Jang, A., Ureno, E., Miller, A., Patrick, S., Duvur, S., Liu, S., Vasiljeva, O., Li, Y., Henriques, T., Badagnani, I., Jeffries, S., Schleyer, S., Leanna, R., Krebber, C., Viswanathan, S., Desnoyers, L., Terrett, J., Belvin, M., Morgan-Lappe, S., Kavanaugh, W. M., & Richardson, J.
- Affiliations
- CytomX Therapeutics (United States) (US)
- AbbVie (United States) (US)
- Corresponding author
- Belvin, Marcia
- ORCID
- Singh, Shweta
- Serwer, Laura
- DuPage, Amy
- Elkins, Kristi
- Chauhan, Niharika
- Ravn, Matthew
- Buchanan, Fritz
- Wang, Leyu
- Krimm, Michael
- Wong, Ken
- Sagert, Jason
- Tipton, Kimberly
- Moore, Stephen J.
- Huang, Yuanhui
- Jang, Andrew
- Ureno, Eric
- Miller, Adam
- Patrick, Sarah
- Duvur, Shanti
- Liu, Shouchun
- Vasiljeva, Olga
- Li, Yingchun
- Henriques, Tracy
- Badagnani, Ilaria
- Jeffries, Shawn
- Schleyer, Siew
- Leanna, Rob
- Krebber, Claus
- Viswanathan, Sridhar
- Desnoyers, Luc
- Terrett, Jonathan
- Belvin, Marcia
- Morgan-Lappe, Susan
- Kavanaugh, W. Michael
- Richardson, Jennifer
- Venue
- Molecular Cancer Therapeutics
- Published
- 2022-06-06
- Volume
- 21
- Issue
- 8
- Pages
- 1326-1336
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC9662867
- OpenAlex
- W4282917798
- Cited by
- 41
- References
- 29
- Citations by year
- 2026: 17 · 2025: 9 · 2024: 11 · 2023: 4
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cancer Therapeutics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- transferrin receptor, antibody-drug conjugates, patient-derived xenografts, cynomolgus monkey toxicity, tumor growth inhibition, undruggable targets, tumor microenvironment
- MeSH terms
- Animals, Antineoplastic Agents, Disease Models, Animal, Humans, Lead, Macaca fascicularis, Neoplasms, Immunoconjugates, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Tumor Microenvironment
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