An antibody-drug conjugate (ADC) is composed of an antibody, a chemical linker, and a small molecular payload, and takes advantage of the specific targeting binding ability of antibody to transport cytotoxic payload to tumor cells (or other target cells). Payload can induce cancer cell apoptosis through mechanisms such as DNA damage or microtubule inhibition, and kill surrounding cancer cells through bystander effect.
The concept of ADC was first put forward by Paul Ehrlich in the early 1910s and described as a “magic bullet”. However, limited by the development bottleneck of antibody preparation and payload coupling technology, the first ADC drug was not approved by FDA until 2000.
Recent years, with the vigorous development of the biopharmaceutical industry and the in-depth research and development of antibody conjugation technology, ADC drugs have ushered in a period of rapid growth. Since 2010, there has been a steady increase in the number of ADC entering clinical trials. At present, a total of 15 ADC products have been approved worldwide. Among the listed products, the reported sales in 2020 are as high as 3.4 billion US dollars.
At present, a total of 9 unlisted ADC products are in the clinical III stage worldwide, among which, Naptumomab estafenatox, developed by NeoTX Therapeutics, completed phase III clinical trials in 2013 but did not reach the main end point. The remaining 8 potential ADC products deserve our attention.
1. Mirvetuximab soravtansine
Mirvetuximab soravtansine (MIRV) is the only ADC drug targeting FR α (folate receptor-α) in clinical stage, which was developed by ImmunoGen and is mainly used for monotherapy or combination therapy for ovarian cancer. The drug composes a humanized anti-FR α monoclonal antibody linked to DM4, a cytotoxin targeting tubulin, through a cuttable sulfo-SPDB linker. ImmunoGen innovatively improved the hydrophilicity of the linker by introducing two methyl groups at the disulfide bond α site and by introducing a sulfonyl group, thus overcoming the disadvantage that the drugs found in the early R&D stage were too unstable in the plasma circulation.
In December 2015, a randomized, open-label, parallel-grouped phase III trial (NCT02631876; FORWARD1) was launched in the United States to evaluate the efficacy of MIRV monotherapy compared to the chemotherapy regimen chosen by the researchers in patients with FR α-positive advanced epithelial ovarian cancer (n=366). In early 2019, published trial results showed that there was no significant difference in progression-free survival (PFS) at the main end point [HR, 0.98; 95% CI, 0.73 to 1.31; PSA 0.897]. The median PFS of the MIRV group and the chemotherapy group was 4.1 and 4.4 months, respectively.
Although the primary end point was not reached, MIRV was observed to be superior to chemotherapy in all secondary endpoints in the high FR α population, including better ORR (24% vs 10%) and CA-125 response (53% vs 25%).
ImmunoGen reported the results of the trial at a Type C meeting with FDA in May 2019, and FDA recommended additional phase III trials to evaluate the efficacy of MIRV in FR α-positive, platinum-resistant ovarian cancer patients. In December 2019, ImmunoGen announced a phase III monotherapy clinical trial program that would include two phase III trials: critical SORAYA trials and confirmatory MIRASOL trials.
In addition to monotherapy, MIRV also carried out clinical studies on combined therapy. Among them, ImmunoGen announced the results of the phase Ib/II clinical trial (FORWARD II) of MIRV combined with bevacizumab in the treatment of platinum-resistant ovarian cancer patients at the 2021 ASCO annual meeting. The results showed that the ORR was 64% in patients with high FR α expression.
In addition, for patients with high FR α expression, the combination therapy also showed excellent performance in median DOR (High FR α 11.8m vs. Medium FR α 8.3m) and median PFS (High FR α 10.6m vs. Medium FR α 5.4m). It was proved that MIRV combined with bevacizumab is effective in the treatment of recurrent ovarian cancer with high FR α.
2. Tusamitamab ravtansine
Tusamitamab ravtansine (SAR-408701) is an ADC product introduced by Sanofi from ImmunoGen, which is a conjugation of cytotoxin DM4 with humanized antibody (SAR408377) targeting CEACAM5 (also known as CD66e) through N-succinimidyl 4-(2-pyridyldithio) butyrate (SPDB) developed by ImmunoGen.
At present, SAR-408701 is the only ADC drug targeting CEACAM5 in the world. Carcinoembryonic antigen-associated cell adhesion molecules (CEACAMs) contain 12 family members (CEACAM1, 3, 4, 5, 6, 7, 8, 16, 18, 19, 20, and 21) and express heterogeneity in normal and tumor tissues.
CEACAM5 has been used as a tumor biomarker since 1965. CEACAM5 participates in intercellular contacts and inhibits loss-of-nest apoptosis through homophilic and heterophilic binding (to CEACAM1 or CEACAM6) with CEACAM5. The inhibitory effect of CEACAM5 on anestrous apoptosis shows that it plays a role in promoting tumorigenesis and metastasis. Studies found that the expression of CEACAM5 is up-regulated in a variety of cancer tissues.
The results of preclinical trials revealed that SAR-408701 showed antitumor activity in a variety of CEACAM5 positive xenograft mouse models (colon cancer, lung cancer, and gastric cancer), and had a clear dose-response relationship. However, the parallel control ADC—SAR3419 with the same linker and DM4 toxin did not show anti-tumor activity.
Currently, Sanofi has released the results of SAR-408701’s phase I/II clinical trial. The open label, non-randomized, parallel distribution, safety, and pharmacokinetic phase I/II trial (NCT02187848) was launched in August 2014. A total of 64 non-squamous NSCLC patients with high expression of CEACAM5 and 28 patients with moderate expression of CEACAM5 were included in the study. The results showed that in the group with high CEACAM5 expression, the disease control rate DCR (PD+SD) was 64%, and the median response duration was 5.6 months (range: 2.0-24.6 months).
In the high CEACAM5 and moderate CEACAM5 expression groups, the overall response rates, the main end points of the trial, were 20% (12.3-31.7%) and 7% (2.0-22.7%), respectively. In addition, exploratory studies also found that patients in the high CEACAM5 expression group who had not previously received microtubule inhibitors showed better disease control (28% vs 15%).
At present, Sanofi is conducting phase III and phase II clinical trials of SAR-408701 monotherapy or combination therapy for NSCLC and other solid tumors.