The Six Gold Standards for Development of Therapeutic Bispecific Antibodies

At present, about 100 therapeutic antibody drugs have been approved by regulatory agencies around the world, and antibody therapeutic drugs have become one of the pillars of the development of new drugs. Among them, monoclonal antibodies (mAbs) have shown clear therapeutic effects in many disease fields, but it is believed that bispecific antibody (bsAbs) can further promote the success of therapeutic antibodies by enabling molecules to have a new mechanism of action (MOA) and providing new functional advantages that mAbs cannot achieve.

A qualified bsAb molecule should be based on three principles: (1) The bsAb molecule can provide unique biological functions, driven by which, it can achieve the expected curative effect; (2) The selected form should enable the molecule to achieve its desired function and to match the biology with the best form; (3) The molecule selected as a candidate for clinical development should meet the six criteria that are critical to clinical development and commercial production, namely, the desired clinical efficacy, safety, pharmacokinetic/pharmacodynamic (PK/PD) properties, physicochemical properties, manufacturability, and minimal or no immunogenicity risk.

1. Physical and Chemical Properties and Manufacturability

Many strategies have been explored to solve the quality problems of chemistry, manufacturing, and controls (CMC), such as mismatch, stability, aggregation, solubility, viscosity, and purification. A desirable bsAb candidate should: (1) be easy to express; (2) have no obvious aggregation or low level of aggregation, because aggregation may affect the efficacy and increase the risk of immunogenicity; (3) be of good solubility and high stability, as well as low viscosity to meet the expected clinical dosage; (4) be relatively low in manufacturing cost.

With the development of bsAb technology, more and more bsAbs can be expressed and purified in a reasonable yield, with reasonable physical and chemical properties for a given clinical application, and can be used for large-scale production, although some of them do require much more CMC optimization and longer development time.

2. Immunogenicity

Immunogenicity is one of the key factors that limit the clinical application of biotherapeutics, because the production of anti-drug antibody may lead to rapid drug clearance, neutralization of the efficacy, and even serious adverse reactions in the clinic. Since most of the reported forms of bsAb are highly engineered with unnatural Ig sequences introduced, bsAbs are likely to have a higher risk of immunogenicity than ordinary mAbs.

Most bsAbs are still in the early clinical stage, and only very limited information can be used to assess the immunogenicity of bsAbs. Because of its serious impact on clinical results, methods have been developed to minimize the risk of immunogenicity in the early detection stage, such as the application of humanized antibodies or fragments, and the assistance of computer-aided design technology.

3. Pharmacokinetic and Pharmacodynamic Properties

Pharmacokinetic and pharmacodynamic (PK/PD) plays an important role in affecting the efficacy and safety of drugs, so it is crucial to the development of bsAb. Many factors of bsAb can affect PK, including molecular form, size, physical and chemical properties, Fc?R binding, and target binding affinity.

The ultimate goal of all strategies to regulate PK is to improve the overall clinical efficacy and minimize the toxicity of therapeutic bsAb. Similarly, the clinical potential of bsAb can be further improved by changing the antigen-binding activity and Fc-mediated effector function, thereby improving PD. Therefore, bsAb PK/PD analysis is necessary and it can be modified by adjusting multiple factors.

4. Effectiveness and Safety

A reasonable efficacy/safety window is the basis of a good clinical candidate; PK/PD, efficacy and safety curves usually influence each other. Drugs that show higher efficacy in the early stage are often selected as therapeutic candidates. However, this kind of drugs often has no or very limited therapeutic window at low-toxic doses, which may seriously hinder their clinical application. Drugs with reasonable efficacy but better safety may have a wider therapeutic window, and the dose can be increased to improve the therapeutic effect without causing obvious toxicity. As mentioned above, increasing drug exposure may be another way to improve efficacy and extend the duration of the response. However, increased systemic exposure may also increase the probability and severity of adverse events.

Based on a strong biological foundation, supported by carefully coordinated bsAb forms and carefully selected binding units, bsAb molecules have just completed the first step towards ultimate success. A qualified bispecific clinical drug candidate not only needs to show good therapeutic potential, but also have to be of desirable physical and chemical properties and manufacturability. In addition, PK properties and low immunogenicity are also the keys to ensuring the success of candidates. In addition to the above factors, the efficacy/safety ratio is the main consideration factor in determining whether a bsAb will eventually enter the development stage.

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