Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

Abstract

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.

Rethinking cancer nanotheranostics

“…However, one main problem of radiation therapy is that some cancer cells are refractory to the treatment. To improve efficacy, chemotherapy is often administered during radiation therapy to sensitize the cancer cells (known as chemoradiation therapy) 63–66 . However, the trade-off of the accompanying chemotherapy is increased systemic toxicity and even increased mortality 67 .…”

An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer

“…Free payloads used in the antibody‐drug conjugate (ADC) technology such as maytansinoids or auristatins are efficient radiosensitizers, but with high off‐target side effects. ADCs that target EGFR or HER2 efficiently radiosensitize esophageal, gastric, head and neck tumor cells . However, clinical trials that tested the combination of anti‐EGFR or HER2 antibodies with gemcitabine for patients with pancreatic cancer did not find any additional benefit compared to gemcitabine alone, thus limiting the use of such antibodies for ADC‐induced radiosensitization in PDAC.…”

“…3 Reducing tumor radioresistance, limiting the exposure of the surrounding normal tissues, and improving tumor control are the major goals to improve radiotherapy efficiency in cancer. Free payloads used in the antibody-drug conjugate (ADC) technology such as maytansinoids or auristatins are efficient radiosensitizers, 4,5 but with high off-target side effects. ADCs that target EGFR or HER2 efficiently radiosensitize esophageal, gastric, head and neck tumor cells.…”

“…ADCs that target EGFR or HER2 efficiently radiosensitize esophageal, gastric, head and neck tumor cells. 5 However, clinical trials that tested the combination of anti-EGFR or HER2 antibodies with gemcitabine for patients with pancreatic cancer did not find any additional benefit compared to gemcitabine alone, 6,7 thus limiting the use of such antibodies for ADC-induced radiosensitization in PDAC. Moreover, ADCs derived from anti-EGFR or -HER2 antibodies should be used with caution due to the skin and heart toxicities observed with the naked antibodies.…”

Radio-sensitising effect of T-DM1 should not be discarded for the efficacy of radiosurgery in the management of brain metastases in patients with HER2-positive metastatic breast cancer

“…However, the clinical utility of potent radiosensitizing drugs is limited by their side effects in practice. There is a recent study reported potent anti-tubulin drugs conjugated to anti-ErbB antibodies; one of them, namely as T-DM1 selectively radiosensitize tumours based on surface receptor expression [2]. The authors showed that concurrent use of T-DM1 with RT prolongs tumour control in tumours overexpressing HER2.…”