Review and Formulation Analysis of 14 Antibody Drug Conjugates (ADCs) Approved by FDA Up To 2022

Since 2000, the research and development of precision therapy represented by small molecule targeted drugs and antibodies has made great progress and become the main targeted therapy for tumors. However, since small molecules and antibody drugs can specifically target tumor signaling pathways or antigens on the surface of tumor cells, and the heterogeneity between tumor cells is strong, precision therapy is very important for precision therapy. ADCs combine the dual advantages of small molecule and antibody drugs compared to antibody or small molecule drugs alone. Many ADCs have demonstrated impressive activity against treatment-refractory cancers, resulting in their approval for both hematologic malignancies and solid tumorindications.

Antibody Drug Conjugates (ADCs) Approved by FDA

After decades of research and troubleshooting, significant technological advancements and an improved mechanistic understanding of ADC activity culminated in the FDA approval of 14 ADCs, each providing demonstrable therapeutic benefit to cancer patients. Currently, about 297 ADCs are in preclinical/clinical development, indicating that the world is ushering in a new era of targeted cancer therapy.

Table 1. FDA approved ADCs currently on the market.

ADC Formulation Analysis

A typical antibody formulation contains ADC, excipients (sugars or salts), buffers, surfactants (Tween) and other metal ion chelators. Table 2 lists the formulations of 14 ADCs, which show that even with the same linker-payload, the final formulation buffer used by different antibodies will be different.

Table 2. ADCs formulation analysis.

The Screening Process and Evaluation Index Analysis of ADC Preparations

pH and Buffer Screening

Among the 14 ADCs on the market, most ADCs have pH values between 6.0 and 6.9. Among them, histidine salt was the most important buffer type. Among the 14, 5 were histidine, 3 phosphate, 2 citrate, 2 succinate, 1 tromethamine and 1 MES. Generally, the selection of ADC buffer needs to follow the following principles: according to the buffer range of different buffer pairs, the pH gradient was set from 4.0-8.0 to prepare the ADC concentration for clinical use. Then, they were placed at 25°C and 40°C for 7 days, observed and sampled on day 0, day 1, day 3 and day 7, respectively, including observation of clarity, BCA detection concentration, SEC-HPLC detection of purity, DSC detection of thermal stability, etc.

When the suitable pH range is determined, two buffers at the pH can be selected. For example, when the suitable pH is 6.0, 30 mM histidine or 20 mM citric acid can be selected as the buffering agent of the preparation, and then the next step is screened.

Table 3. ADCs pH and buffer analysis.

Surfactant Screening

Surfactants reduce aggregate production primarily by reducing surface tension. Of the 14 ADCs, 7 used 0.01-0.02% (W/V) Tween 80, 3 used 0.01-0.02% (W/V) Tween 20, and 1 used 0.03% Tween 80, 1 used 0.1% Tween 20, and the other 2 did not add surfactant. Generally, there are two screening principles for surfactants.

• Common processing method: stir the sample horizontally at 250-300 rpm on an orbital shaker at 25°C for 8 hours or longer. After stirring, some samples will aggregate and the solution will become cloudy.
• Reference detection methods: visual observation of solution clarity, concentration determination, SEC-HPLC detection of aggregate content, turbidity meter detection of turbidity, HIAC automatic liquid particle counter detection of particle number.

Excipient Screening

Among the 14 ADC formulations, various sugars or salts were added as excipients mainly. When setting different sugars and salts, there are many combinations and types. 10% trehalose, 9% sucrose, 5% sorbitol, etc. can be used as the basic formula for preliminary screening. When it is necessary to combine, the content of the two is halved. After 14 days of storage at 4°C, 25°C, and 40°C, characterizations were performed for transparency observation, BCA concentration detection, SEC-HPLC purity detection, DSC thermal stability detection, CIEF pH detection, etc.

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Review and Formulation Analysis of 14 Antibody Drug Conjugates (ADCs) Approved by FDA Up To 2022

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