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Tian Wenzhi: The design of bispecific antibody molecule should be "simple" and the target selection should be based on scientific cognition

Tian Wenzhi: The design of bispecific antibody molecule should be "simple" and the target selection should be based on scientific cognition

 Author | Tian Wenzhi, founder of ImmuneOnco

 In recent years, dual/multi-target antibodies have become a hot spot in the field of biomedicine research and development. Almost all biopharmaceutical research and development companies from abroad to China are laying out dual/multi-target antibody projects, which include both technology platform development and drug development based on other people's technology platform. In this paper, the scientific thinking of developing double/multi-target antibodies and the future trend of development are discussed on the basis of personal understanding of this field.

Double-target antibodies (abbreviated as "bispecific antibodies") refer to two different epitopes of an antibody molecule targeting two antigens or one antigen at the same time. Because of the complexity of diseases (especially tumors), the efficacy of targeting a disease antigen is often limited. At the same time, the combination of antibodies targeting two disease antigens brings better synergistic effect, which promotes people's enthusiasm for " bispecific antibodies".

Up to now, there are three "bispecific antibodies" drugs approved for market. One is Catumaxomab, which targets EpCAM and CD3. It was approved in the European Union in 2009 for the treatment of advanced ovarian cancer patients with ascites. It was withdrawn in June 2017 because of its poor efficacy.

The second is Blinatumomab, which targets CD19 and CD3. It was approved by FDA of the United States and EMA of the European Union in 2014 and 2015 respectively for the treatment of acute B-lymphoblastic leukemia.

The third is Emicizumab, targeted coagulation factors IX and X, which were approved by FDA and EMA in November 2017 and March 2018 respectively for the treatment of hemophilia A (Editorial Note: Emicizumab was listed in China in December 2018). At present, there are 57 "bispecific antibodies" drugs in clinical trials.


Thinking about the bispecific antibodies Platform


There are many "bispecific antibodies" technology platforms in the R&D stage, which can be roughly divided into two categories: one with Fc and the other without Fc. The "bispecific antibodies" technology platform with Fc includes TrioMab, Crossmab/KIH, DVD-Ig, IgG-scFv, FIT-Ig, mAb-Trap and so on. The"bispecific antibodies" technology platform without Fc includes BiTE, DART, TandAb, ImmTAC, TriKE and so on.

The technology platform with Fc has the advantages of convenient purification and good stability, but the disadvantage is that some structures (such as Crossmab/KIH) CMC are more complex, and most of them have higher polymer, mismatch, low purification yield and so on. In addition, if the molecular weight is too large, the permeability of the tumor tissue will be poor.

                                                   Technical Platform with Fc


      The technology platform without Fc is mostly based on the link of two single-chain antibodies designed by CD3 antibody. It has the advantages of high yield and low clinical dose. But without Fc, the conventional purification technology based on Protein A can not be used, and a specific purification technology route must be developed. In addition, the half-life of these molecules is relatively short, only a few hours (for example, Blinatumomab, only 2 hours), which requires frequent use of drugs.

 

                                                    Technological Platform without Fc


     After clinical verification, there are three "bispecific antibodies" technology platforms: TrioMab, Crossmab/Knock-Into-Hole, and BiTE. Since Catumaxomab has been withdrawn from the market, strictly speaking, only two "bispecific antibodies" technology platforms have been clinically verified. Other platform products are in the early and mid-term clinical trials.

     Many factors (indications, corresponding targets, pharmacokinetics, etc.) need to be taken into account when designing the "bispecific antibodies" molecule.

      For example, if the indications are for autoimmune diseases (such as RA, psoriasis) or hematological tumors, because the disease target (mostly cytokines, such as IL-1, IL-17, IL-23, TNF-a) or cancer cells are moving in the blood, the permeability of drugs can be ignored, and Fc can be chosen in the molecular structure design.

     If it is aimed at solid tumors (such as lung cancer, stomach cancer, colorectal cancer, etc.), excessive molecular weight may affect the bioavailability of the "bispecific antibodies" drugs, and thus affect the efficacy. herefore, the pharmacokinetics in vivo should be fully considered in molecular design, and a pre-pharmacokinetic experiment should be done if necessary to ensure that the drugs are available. Tissue permeability and relative bioavailability.

      In conclusion, the design of the molecular structure of the "bispecific antibodies" should be based on the principle of "simplicity" to ensure that there are no polymers, no mismatches, purified yield and good pharmacokinetics in the molecular structure.


Thinking about Target Selection


     When selecting the target of the “bispecific antibodies” molecule, it should be based on the results of scientific cognition and experimental verification. If it is a "double-antibody" drug for tumors, the biological functions of two targets should be considered. Generally, it can be divided into three types:

      Both targets were expressed in cancer cells.

      One in tumor cells and the other in immune cells.

      Both are in immune cells.

    The "bispecific antibodies" drugs with both targets in cancer cells have not yet been approved and are currently in clinical trials. It mainly includes Duligotuzumab (MEHD7945A, targeted EGFR/Her3), MM-111 (targeted Her2/Her3), LY3164530 (targeted Met/EGFR), JNJ-61186372 (JNJ-372, targeted EGFR/c-Met), ABL001 (NOV1501, targeted VEGF/DLL4), etc.

    The fastest progress was Duligotuzumab, who completed phase II of the clinical trial. Unfortunately, the trial failed and did not reach the end of the clinical trial. LY3164530 also terminated the clinical trial because EGFR inhibited the related toxicity.

    One of the CD3-based "bispecific antibodies" drugs has been approved for market (Blinatumomab), while the other 34 are in different clinical trials, including 18 blood tumor targets and 16 solid tumor targets. MGD019 (DART, targeted PD-1/CTLA-4) is the "bispecific antibodies" molecule targeting two immune cells (mainly T lymphocyte). It has just entered phase I clinical trials, and no results have been obtained.

     In my opinion, the following aspects should be paid attention to in the development of "bispecific antibodies" drugs for cancer indications:

    Starting from the microenvironment of tumors, the microenvironment characteristics of each solid tumour were analyzed.

      Focus on the low reactivity and tolerance of antibody drugs at existing immune checkpoints.

     The design of “bispecific antibodies” molecule should be considered in combination with both tumor cells and immune cells.

     At present, there are no successful cases of "bispecific antibodies" drugs aimed solely at tumor targets.

      At present, there are no successful cases of "bispecific antibodies" drugs targeting only immune cells.

      How to increase the number of immune cells in tumor microenvironment (combined with chemokines);

      How to reduce the number of immunosuppressive cells (Treg, M2) in tumor microenvironment.


Future Trends


     Because of the specific pharmacodynamic advantages of "bispecific antibodies" drugs, there will be vigorous development in the future. Especially with the gradual recognition of Blinatumomab and Emicizumab by the market and industry, the development of "bispecific antibodies" drugs based on scientific mechanisms (such as the synergistic effect of two single-target antibodies and the substitution of functional molecules) will have a bright future.

     But this does not mean that a bomb-grade "double-antibody" or "multi-antibody" drug can be developed casually. Especially for "multi-antibody" drugs, the proprietary drug should be a big problem.

   For example, in this year's ASCO abstract, a new type of four-specific antibody (PD-1/CD47/VEGF/TGF-beta) calculated and designed by Chinese scientists has been published. In theory, multi-target means biological activities related to multiple targets, which may lead to better efficacy, but at the same time, more serious clinical safety problems will arise.

     But from the perspective of scientific thinking, I do not think that "multi-antibody" drugs will become a trend in a short time, because it involves many insurmountable scientific difficulties, such as the establishment of multi-target humanized mouse model, whether it can be effectively used for in vivo pharmacodynamic evaluation, let alone large animal safety evaluation research.


Reference

1. Christian Klein, Wolfgang Schaefer, and Jeorg T.Regula. The use of CrossMAb technology for the generation of bi- and multispecific antibodies. MABS. 2016, VOL. 8 (6):1010–1020

2. Frans V. Suurs , Marjolijn N. Lub-de Hooge , ElisabethG.E. de Vries, Derk Jan A. de Groot. A reviewof bispecific antibodies and antibodyconstructs in oncology and clinical challenges. Pharmacol Ther. 2019, S0163-7258(19)30069-5.