Alex Dean

Combined Immunotherapy for Breast Cancer

Blog Post created by Alex Dean on Sep 28, 2018

Breast cancer is the most common type of cancer in women. It is estimated that the annual number of new breast cancer cases is 1.7 million, of which 15%-20% are three-negative types, which means that these patients lack the three expression of tumor-associated proteins that can be targeted by therapeutic drugs.

 

SGN-LIV1A, a novel targeted therapy for breast cancer

 

In 2017, US biotechnology company Seattle Genetics said that the company has entered into a clinical research cooperation agreement with Roche's subsidiary Genentech. The two companies will conduct a study on the combined use of SGN-LIV1A, an antibody-conjugated drug, and atezolizumab (TECENTRIQ®) for the treatment of metastatic triple-negative breast cancer (TNBC). SGN-LIV1A is one of the four antibody-drug conjugates being developed for solid tumor therapy by Seattle Genetics, and it is composed of monoclonal antibody targeting LIV-1 and cytotoxic monomethyl auristatin E ( MMAE).

 

As viewed by the senior Vice President of Clinical Development at Seattle Genetics Dr. Robert Lechleider, the challenge of triple-negative breast cancer treatment is that there is still a lack of available targeted therapies. Patients with this type of cancer have generally poor prognosis. At the same time, the effectiveness of existing treatments is limited and can only delay disease progression. The clinical phase 1 trial showed that SGN-LIV1A monotherapy is still active in patients with metastatic triple-negative breast cancer who have received multiple treatments. The study cooperated with Genentech will mainly focus on the clinical efficacy of atezolizumab in combination with SGN-LIV1A in the treatment of triple-negative breast cancer."

 

The clinical collaboration to be carried out by these two companies is a clinical Phase 1b/2 trial for second-line treatment of patients with metastatic breast cancer who have not previously received immunotherapy. This randomized, controlled study is expected to recruit 45 patients in the treatment group, and Seattle Genetics and Genentech will collaborate on MORPHEUS, the innovative cancer immunotherapy development platform of Roche, which is designed to rapidly and effectively develop cancer combination therapies.

 

Under the cooperation agreement between the two parties, Genentech will be responsible for the operation of this clinical 1b/ 2 trial, and Seattle Genetics for the global development and commercialization of SGN-LIV1A.

 

SGN-LIV1A is a novel therapeutic drug targeting LIV-1 protein designed using Seattle Genetics' patented ADC platform. LIV-1 is expressed in most metastatic breast cancer cells and is also detected in other tumor types, including melanoma, prostate cancer, ovarian cancer, and uterine cancer. SGN-LIV1A links the LIV-1 targeting monoclonal antibody to the microtubule disrupter monomethyl auristatin E (MMAE) by a protease cleavage linker similar to the technique used by ADCETRIS (brentuximab vedotin). SGN-LIV1A targets LIV-1 in cancer cells and releases drugs in cells. SGN-LIV1A may also produce anticancer activity through other mechanisms of action such as activation of immune responses.

 

Antibody-drug Conjugate

The Antibody drug conjugate selectively and continuously delivers cytotoxic drugs to the tumor. It is composed of antibodies, ADC Cytotoxin and ADC linker. Many monoclonal antibodies are standard therapies for solid tumors and hematological cancers, while primary chemotherapy drugs have limited therapeutic effects on cancer due to their non-specific toxicity. Therefore, the discovery of ADC fills the gap between the two. Mylotarg is the first FDA approved ADC for acute myeloid leukemia. Adcetris is a conjugate of the CD30 antibody and monomethyl auristatin E and is approved for the treatment of lymphoma. Kadcyla has been commercialized for HER-2 positive metastatic breast cancer. The challenges faced by ADCs include antibody immunogenicity, antigen expression, premature drug release, etc., but luckily, progress in bioengineering has improved its safety and efficacy.

 

 

Cytotoxic load characteristics of ADCs

  1. 1. Efficient therapeutic index, also effective at low doses. It kills cancer cells without killing healthy cells.
  2. 2. Stable in the blood circulation (due to intravenous administration).
  3. 3. Can be coupled with the linker while retaining the internalization properties of Ab and promoting its anti-tumor effect.
  4. 4. Classification: microtubule inhibitors, DNA synthesis inhibitors, and fupoisomerase inhibitors. It should be noted that inhibitors are a well-established class of drugs that have long been used.

 

ADC's technological advancement

A diverse, new and safer ADC is always the aim. The first generation of ADC is murine antibody and has greater immunogenicity, low antigen specificity, insufficient toxic load, and unstable joints. For this reason, the related drug Mylotrag has been withdrawn. The second-generation ADCs are more stable than the first-generation connector, and the toxic load is more effective as well, but based on the random coupling strategy, the DAR is heterogeneous, the drug stability is low, the non-specific toxicity is increased, and the half-life of the ADCs is reduced. Site-specific coupling is the characteristic of the third generation of ADC, which has more effective cytotoxic carrier. To sum up, a lot of efforts are still needed in the drug design of targeted therapy against various cancers.

Outcomes