George L․ Kumar, Senior Director at AstraZeneca, shared a post LinkedIn:
“What if two antibodies could find each other and assemble a cancer drug – inside the body, after you’ve already dosed the patient?
Antibody–drug conjugates (ADCs) have reshaped oncology by delivering potent cytotoxic payloads straight to tumour cells. But they carry a built-in limitation: each ADC hunts for a single target antigen. In heterogeneous tumours – where that antigen is expressed unevenly, weakly, or not at all – targeting breaks down and resistance takes hold.
A new preclinical study introduces a clever way around that ceiling: build the therapeutic construct in vivo, using click chemistry.
Here’s the idea:
- Tag a therapeutic antibody with one bioorthogonal handle (trans-cyclooctene) and an ADC with its chemical partner (tetrazine).
- Administer them sequentially. Once both are circulating, the two halves ligate to each other in the body – forming a functional antibody–ADC “click” construct at the tumour.
- The result is a drug assembled on site, no extensive antibody re-engineering required.
Why it matters: in models co-expressing HER2 and EGFR, this antibody–ADC click approach outperformed standard ADC monotherapy and simple antibody-plus-ADC combinations. Crucially, it showed activity in tumours with low, ultralow, negative, or heterogeneous HER2 expression – precisely the cases that are resistant to, or ineligible for, conventional HER2-directed ADCs.
For those of us working in biomarker scoring and companion diagnostics, this is a compelling shift. So much of our effort goes into stratifying patients by expression thresholds. A modular platform that engages receptor biology across a spectrum of expression levels – and extends to other receptor pairs – could reframe how we think about eligibility, heterogeneity, and resistance altogether.
The payload isn’t the only thing that matters. Increasingly, it’s the chemistry that decides where and how the payload comes together.”
Title: Modular in vivo antibody–ADC click to reverse drug resistance in tumours
Authors: Cristina Simó, Alexander Vanover, Ricardo Albanus, Sandeep Panikar, Shayla Shmuel, Alex Benton, Jader Giraldo-Guzman, José Luna, Yifei Xu, Na-Keysha Berry, Nai Keltee, Jingxia Liu, Farrokh Dehdashti, Patrícia Pereira
Read the Full Article.
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