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Bicycle vs ADC as drug delivery system
Recently, a company in England called Bicycle Pharmaceutical announced Phase 1/2 clinical trial for BTC BT8009 for advanced bladder cancer. BTC BT8009 is a targeted chemotherapy just like PADCEV which Heath Canada had approved in January, 2022. As a matter of fact, BTC BT8009 and PADCEV are almost the bladder cancer treatment in such that both treatments target Nectin-4, which is a cell adhesion molecule from the Nectin and Nectin-like family, that is known to be overexpressed in tumor cells and hypothesized to be an important player in tumor cell growth and proliferation. Furthermore, both treatments use the cytotoxin MMAE as the chemo agent to disrupt microtubules formation during Mitosis phase in the cell cycle for cell division, which leads to apoptosis – cell death. So, what’s the difference between PADCEV and BTC BT8009? The difference is in its drug delivery system. PADCEV uses antibody as the vehicle to reach to NECTIN-4 on cancer cells. The antibody PADCEV uses is similar to what our immune system generates when our body is invaded with pathogens, but the antibody was designed to target only NECTIN0-4, so it is called monoclonal antibody. The name of a drug which utilizes monoclonal antibody as the drug delivery system is often ends with “MAB”. So, the scientific name of PADCEV is Enfortumab vedotin. Vedotin is another name for the cytotoxin MMAE. The drug which uses antibody as the delivery vehicle with payload of cytotoxin to kill cancer cells is called “Antibody Conjugated Drug” or ADC. PADCEV is ADC with payload of cytotoxin MMAE. Once PADCEV is administered intravenously, it goes all over our body where blood reaches, then the monoclonal antibody binds to NECTIN-4 on cancer cells, then releases the cytotoxin MMAE inside the cytoplasm of the cancer cell.
Antibodies are heavy (150 kDa) proteins of about 10 nm in size, arranged in three globular regions that roughly form a Y shape ** Wikipedia Antibody is made up with over 600 amino acids. ADCs are classified as macro molecule. So, it takes long time to develop monoclonal antibodies (mABs). mAbs developed in the 2004-2011 time period spent an average of 2.4 years in Phase I trials, 2.2 years in Phase II trials and 2.7 years in Phase III trials, followed by about a year of FDA review, on average ** Biotechnology Innovation Organization.
Key properties of Bicycle(R) bicyclic peptides are listed below.
1. Short peptides consisting of nine to 15 amino acids 2. Chemically synthesized 3. Low molecular weight (1.5-2kDa), delivering attractive PK and rapid tissue penetration 4.Large molecular footprint allowing protein-protein interactions to be targeted 5. Renal elimination, minimizing potentially deleterious bystander cell interactions in liver and gut. 6. No immunogenicity observed to date 7. Versatility for multimerization and conjugation 8. Classified as small molecules by regulatory agencies 9. Scalable and controllable manufacturing using established methodologies
The company termed their Bicycle(R) as vehicle to deliver cytotoxin to cancer cells as “Bicycle conjugated drug ” which conjugates are tripartite molecules that use a Bicycle to recognize and bind to a specific tumor antigen, a selectively cleavable linker only cleaved by enzymes within the tumor microenvironment and a small molecule payload. The linker and coupling chemistry hold the payload inert until the conjugate is localized in the tumor microenvironment, delivering payloads into solid tumors with extensive tissue penetration, a short duration of systemic exposure and liver-sparing rapid renal elimination. These properties limit the body’s exposure to payload to minimize any damage to normal tissue. The first target for bladder cancer the company chose was NECTIN-4 and the first cytotoxin the company chose was MMAE, both did not infringe upon the patent related PADCEV.
Thee interim trial results of BTC BT8009 were reported in April, 2022 AACR (American Association for Cancer Research) Annual Meeting. The results are as follows.
“As of March 7, 2022, thirty-seven patients have been dosed in the Phase I/II trial of BT8009. A total of twelve response evaluable urothelial cancer (UC) patients have been dosed in monotherapy cohorts of 2.5mg/m2 and 5.0mg/m2 weekly in the ongoing trial.
Four response evaluable UC patients were dosed at 2.5mg/m2 weekly. Among these four patients, one patient was observed to have tumor reductions constituting a confirmed partial response (PR) and two patients were observed to have stable disease (SD), reflecting a 25% overall response rate (ORR) and 75% disease control rate (DCR) in patients in this cohort.
Eight response evaluable UC patients were dosed at 5.0mg/m2 weekly. Among these eight patients, four patients were observed to have a confirmed complete response (CR) or PR, including one patient with a CR and three patients with a PR, and two patients with SD, reflecting a 50% ORR and a 75% DCR in UC patients for this cohort. Prior to enrollment, all patients in this cohort had previously received at least two prior lines of therapy, with a median of three.
The median duration of response has not yet been reached in either the 2.5 mg/m2 or 5.0mg/m2 cohort. Four of the five responders have ongoing Response Evaluation Criteria in Solid Tumors (RECIST) tumor responses. As of the March 7, 2022 data cutoff date, all four of these patients have a treatment duration of at least 24 weeks and all four remain on therapy.
Tolerability profile remains consistent with earlier results from this trial. No dose limiting toxicities have been observed in the 2.5mg/m2 or the 5.0mg/m2 cohorts, and with longer-term follow-up, incidence of skin and eye toxicity, neuropathy and hyperglycemia remains low.
Phase I dose escalation is ongoing. Exploration of additional doses and frequencies continues, and Bicycle intends to provide further updates this year.
Next, the images of Antibody molecule, Antibody Conjugated Drug, Bicycle Molecule, Bicycle Conjugate Drug.
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Images of Antibody-drug conjugate molecule.
In case of PADCEV, Target antigen is NECTIN 4 on cell membranes. Monoclonal Antibody is the vehicle to reach the target antigen (NECTIN-4). Cytotoxic drug is MMAE. Linker is to control release of MMAE inside cancer cells.
The cell cycle – Cancer cells die in Mitosis (Cell division phase) by the chemo agent MMAE which was released into the cell.
MMAE disrupts formation of microtubules which are formed during METAPHASE in Mitosis. This leads to Apoptosis – the death of the cell.
Bicycle based drug conjugate – Structure. I could not find other images related the structure . BTC is short for Bicycle Toxin Conjugates (R). BTC for bladder cancer targets NECTIN-4 on cell membrane, and releases cytotoxin MMAE inside the cell. Once MMAE is released inside the cell, mechanism of killing the cell is exactly the same as PADCEV,
So, another drug has been approved in April, 2022 by FDA for advanced and metastasized bladder cancers. The drug is called sacituzumab govitecan (Trodelvy) by Gilead Sciences, Inc.. Trodelvy is another Antibody Drug Conjugate (ADC) targeted chemotherapy. So the drug delivery mechanism is the same as PADCEV. The difference is that Trodelvy uses TROP-2 instead of NECTIN-4 as the target which is also highly expressed on the cell membrane of cancer cells including bladder cancer cells. Once Trodelvy binds to TROP-2 protein on the surface of bladder cancer cells, it infuses the cytotoxic chemo agent called SN-38, a topoisomerase I inhibitor. Topoisomerase I is the enzyme which unwind cramped DNA before DNA is replicated during the cell division. This unwinding of DNA happens in S phase of the cell cycle. So, SN-38 – topoisomerase I inhibitor prevents the cramped DNA from unwinding, thus interrupts DNA replication, which leads to the cell death.
The clinical trial showed that Trodelvy worked even for the patients who were treated with PADCEV. It means Trodelvy can be used as the 4th line of treatment for advanced and metastasized bladder cancer following, platinum based chemotherapy as the 1st line, immunotherapy as the second line, PADCEV as the 3rd line, then Trodelvy as the 4th line treatment. What FDA approved is that Trodelvy as a treatment for patients whom immune checkpoint inhibitors immunotherapy did not work.
Note that Trodelvy had been approved already in 2021 as the first line class treatment for breast cancer.
We hope Trodelvy is also approved in Canada soon.
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