Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

Abstract

DDR1 has been identified as a cancer‐associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi‐kinase inhibitors, such as nilotinib, inhibit DDR1‐mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody‐based strategy with a novel anti‐DDR1 antibody‐drug conjugate (ADC) for colon carcinoma treatment. We developed T 4 H 11 ‐DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro , T 4 H 11 ‐DM4 exhibited potent anti‐proliferative activity with half maximal inhibitory concentration (IC 50 ) values in the nanomolar range in a panel of colon cancer cell lines. In vivo , the antitumor efficacy of T 4 H 11 ‐DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T 4 H 11 ‐DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg −1 in HT‐29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T 4 H 11 ‐DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T 4 H 11 ‐DM4 was efficacious in oxaliplatin‐resistant colon cancer models. In exploratory safety studies, T 4 H 11 ‐DM4 exhibited no overt toxicities when multi‐doses were administered at 10 mg·kg −1 into BALB/c nude mice or when a single dose up to 50 mg·kg −1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1‐targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer

“…Finally, DDR1 inhibition displays antitumor activity in mice that have already developed DDR1dependent metastatic nodules, revealing an additional important DDR1 role in metastatic growth (42). Consistently, DDR1 expression level is associated with shorter overall survival in patients with mCRC, and DDR1 phosphorylation is strongly increased in the corresponding metastatic lesions (42,43). Interestingly, DDR1 upregulation is an independent marker of poor prognosis in patients with stage IV CRC, and is not correlated with any CMS subtype (42).…”

“…Due to DDR1 aberrant expression in CRC, an anti-DDR1 antibody-drug conjugate was recently developed for CRC treatment. This agent displayed significant anti-tumor activity in a preclinical model of CRC, without overt toxicity in control animals ( Table 1) (43). Finally, small-molecule allosteric inhibitors of DDR2 extracellular domain inhibit the tumormicroenvironment interaction and breast tumor invasion (70).…”

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

“…For instance, DDR1 mAb 48B3 can prevent the invasion and adhesion of G140 human glioma cells 67 . In 2019, Tao et al 68 developed a DDR1 antibody DM4 (an anti–tubulin agent blocking cell division) drug conjugate called T4H11‐DM4, which can suppress colon cancer tumorigenesis in vitro and in vivo.…”

LRP-1 Promotes Colon Cancer Cell Proliferation in 3D Collagen Matrices by Mediating DDR1 Endocytosis

“…However, other studies have demonstrated that, in breast carcinomas, DDR1 promotes apoptosis through induction of pro-apoptotic protein BIK1 (Assent et al, 2015;Saby et al, 2018Saby et al, , 2019. In the case of CRC, recent studies have shown that nilotinib, a specific inhibitor of DDR1 phosphorylation, strongly reduced DDR1-mediated CRC cell invasion and metastasis in mouse models (Jeitany et al, 2018), and that the use of antibodydrug conjugates targeting DDR1 exhibits antitumor effects in a mouse model of CRC (Tao et al, 2019). These works have been carried out on CRC cells harboring invasive-like phenotype.…”