What Is Antibody-drug Conjugate?

what is an antibody drug conjugate? Antibody drug conjugate (ADC) is a biologically active cytotoxic drug linked to a monoclonal antibody (mAb) by a chemical bond, and a monoclonal antibody (mAb) is used as a carrier to transport the cytotoxic drug to the target cells. This novel drug has brought a new trend in the field of cancer treatment and aroused interest of more and more people. So what are the features and history of ADCs and why are they valued by researchers and investors?

1. Features

Antibody drug conjugate (ADC) combines the powerful killing ability of cytotoxic drugs with the high targeting, stability and favorable pharmacokinetic characteristics of recombinant monoclonal antibodies (mAbs), characterized by strong therapeutic effect, high specificity, weak immunogenicity, not easy to produce drug resistance, and long circulating time in serum (shorter than monoclonal antibody).

1. Development history

As early as the beginning of the 20th century, medical scientists represented by Paul Ehrlich, the father of chemotherapy, proposed the inference of the "magic bullet" to find a compound that can selectively target pathogenic organisms without other side effects. The concept of ADCs was proposed in 1958, but at that time the technology was lagging behind. Until 1975, the first modern version of ADCs was reported. With the development of humanized targeted antibodies, increased cytotoxic drug activity, new linker stability, and increased cleavage efficiency, the development of ADCs has also entered a golden age.

In 2000, the FDA approved the first ADC to be marketed (trade name Mylotarg), developed by Pfizer for the treatment of patients with first recurrence, over 60 years of age, CD33+, and patients with acute myeloid leukemia (AML) who are not suitable for cytotoxic chemotherapy). Mylotarg was found to have severe fatal liver damage in a post-marketing confirmatory phase III study and did not show significant survival benefit.

After Mylotarg, four other ADCs have been approved by the FDA for approval: Adcetris (brentuximab vedotin, jointly developed by Takeda/Seattle Genetics, 2011, for the treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoid, Knox's Kadcyla (HER2 ADC, 2013, for the treatment of HER2-positive breast cancer); Wyeth/Pfizer's Besponsa (inotuzumab ozogamicin, 2017, for monotherapy for relapsed or refractory CD22+ adult B Cell precursor acute lymphoblastic leukemia (ALL)). AstraZeneca's Lumoxiti (moxetumomab pasudotox-tdfk, 2018, is used to treat adult patients who have received at least two systemic, relapsed or refractory hairy cell leukemia (HCL).) And in September 2017, Mylotarg was approved by FDA for re-marketing for the treatment of newly diagnosed CD33+ adult acute myeloid leukemia (AML), as well as refractory CD33+ acute myeloid leukemia (AML) in children over 2 years of age who did not respond to initial treatment.

1. Future prospects

Recently, Seattle Genetics and Astellas jointly announced the use of the antibody-drug conjugates enfortumab vedotin for the treatment of locally advanced or metastatic urothelial cancer, in a critical phase 2 trial EV- In the patient of cohort 1 of 201, a positive top line result was obtained. Patients in this cohort had previously received platinum-based chemotherapy and treatment with PD-1 or PD-L1 inhibitors. In view of the significant improvement in objective response rate (ORR) in this trial, the two companies plan to submit biologics license applications (BLA) to the FDA based on the results of the EV-201 trial (queue 1) later this year. Phase 3 trials will continue to support global outreach.

The development of ADC is closely dependent on the discovery of new targets, the optimization of antibody modification technology, the development of small molecule toxins and the improvement of coupling technology. The goal of evolution has always been the expansion of therapeutic windows, especially the improvement of safety. The development of domestic ADCs should further seek differentiated targets. International ADC manufacturing company has introduced a number of improvements and innovations in new small molecule toxins, polymer coupling agents, improved release mechanisms, improved water solubility, site-directed coupling, and increased drug loading. Adcetris has been approved by FDA for the use of chemotherapy, and clinical trials of other ADCs have increased. ADC technology has also been shown in non-tumor areas, such as the coupling of antibacterial drugs. SMDC (which converts antibodies from ADCs to small molecule ligands), similar to ADC, is currently in the clinical trial stage of oncology drugs, medical imaging, and CAR-T.