What is ADC in biologics?

Antibody-drug conjugates (ADCs) are an important class of biologics used in targeted cancer therapy. ADCs utilize the specificity of monoclonal antibodies to deliver potent cytotoxic drugs directly to cancer cells.

What are ADCs?

ADCs are complex molecules composed of three key components:

• A monoclonal antibody that binds specifically to a target antigen on the cancer cell surface
• A cytotoxic drug or payload that has anticancer activity
• A chemical linker that attaches the drug to the antibody

The monoclonal antibody component of an ADC enables specific targeting of cancer cells that express the antigen target. The cytotoxic payload kills these cancer cells after the ADC binds to the antigen and gets internalized. The linker keeps the highly potent payload stable in circulation and releases the drug inside the cancer cell. This approach aims to maximize antitumor activity while minimizing off-target toxicity.

How do ADCs work?

ADCs exploit the specificity of monoclonal antibodies to selectively deliver cytotoxic drugs to tumor cells. The mechanism of action involves several steps:

1. The ADC circulates in the bloodstream and binds to its target antigen on the cancer cell surface.
2. The ADC-antigen complex gets internalized into the cell via endocytosis.
3. Inside the cell, the linker releases the cytotoxic drug from the antibody in response to the acidic environment of endosomes/lysosomes.
4. The freed cytotoxic drug binds to its intracellular target and disrupts critical cell processes, leading to cancer cell death.

Therefore, ADCs combine the precision of monoclonal antibodies with the cell-killing ability of chemotherapeutic agents. The cytotoxic payload is only unleashed inside cancer cells, improving efficacy and safety.

What are the components of an ADC?

Monoclonal antibody

The monoclonal antibody component is essential for the tumor-targeting ability of ADCs. The ideal antibody target should be:

• Highly expressed on cancer cells but low/absent on healthy cells
• Internalized rapidly after antibody binding
• Not shed into circulation from cell surface

Accessible in solid tumors

Common antibody targets for ADCs include growth factor receptors like HER2, EGFR, and VEGFR as well as cell surface proteins like STEAP1, CD30, and PSMA.

Cytotoxic drug

ADCs employ highly potent cytotoxic agents that would be too toxic to administer systemically in untargeted form. The payload needs to be:

• Cytotoxic at picomolar to nanomolar concentrations
• Amenable to chemical conjugation and stable linkage
• Adequately soluble and stable in circulation

Some examples of ADC payloads are auristatins, maytansinoids, calicheamicins, duocarmycins, and pyrrolobenzodiazepines.

Linker

The linker connects the monoclonal antibody to the cytotoxic drug. Linker properties influence ADC stability, pharmacokinetics, and drug release inside cells. An ideal linker should:

• Be stable in circulation to prevent premature drug release
• Release the cytotoxic drug efficiently inside cancer cells
• Cleavable by tumor cell enzymes like proteases or in endosome/lysosome
• Allow good conjugation chemistry and reproducible synthesis

Common ADC linkers include hydrazones, disulfides, peptides, and succinimide-based structures.

How are ADCs designed and optimized?

Developing an optimal ADC involves careful selection and engineering of the antibody, linker, and drug components. Key parameters for ADC design include:

• Antigen binding – The antibody needs high specificity and affinity.
• Drug-to-antibody ratio (DAR) – Varying DAR from 2-8 drugs per antibody can modify pharmacokinetics, efficacy and toxicity.
• Conjugation chemistry – The linker is attached via lysine, cysteine or engineered glycan residues on the antibody.
• Linker stability – Tunable to balance circulation stability with efficient drug release inside cells.
• Drug potency – High cytotoxicity (picomolar/nanomolar IC50) needed for efficacy.

ADC developers use advanced protein engineering and cell-based screening methods to select optimal configurations. The final ADC product should display good manufacturability, stability, pharmacokinetics, and therapeutic index in preclinical models.

What are the key steps in manufacturing ADCs?

ADC manufacturing involves complex multi-step processes for constructing a homogeneous, stable product. Key steps include:

1. Monoclonal antibody production – Antibodies generated via cell culture of engineered mammalian cell lines.
2. Purification – Isolation and purification of the antibody molecule.
3. Drug conjugation – Covalent linkage of cytotoxic drugs via engineered cysteines, lysines or glycans on the antibody.
4. Purification of ADC – Isolation of the final ADC product from unconjugated components and impurities.
5. Formulation – ADC stabilized in appropriate buffers and excipients.
6. Fill/finish – Aseptic dispensing into vials or syringes.

Stringent quality control is implemented at each step to ensure a pure, homogenous, and potent ADC product. Glycan-based conjugation strategies enable more consistent ADCs compared to cysteine/lysine techniques.

What analytical methods are used to characterize ADCs?

A wide array of analytical methods are utilized to extensively characterize ADCs at each step of development and manufacturing, including:

• Mass spectrometry – Determines DAR, conjugation sites, payload distribution.
• Chromatography – Quantitates unconjugated antibodies and free drug.
• Capillary electrophoresis – Monitors antibody integrity and changes.
• UV/Vis spectrophotometry – Measures drug-to-antibody ratio.
• Binding assays – Confirm retained antigen binding affinity.

Stringent specifications for purity, homogeneity, stability, and potency are established using these analytical techniques during ADC optimization and manufacturing.

What are the challenges in ADC development?

Key challenges in designing and producing ADCs include:

• Identifying optimal antibody targets – Ideal targets highly expressed on cancer cells while sparing normal tissue.
• Engineering stable, homogenous ADCs – Linker chemistry and DAR can significantly impact ADC properties.
• Ensuring specificity – Off-target toxicity limits therapeutic window.
• Achieving sufficient intratumoral drug levels – Delivery challenges due to solid tumor barriers.
• Minimizing toxicity – Toxicity from off-target effects or premature drug release.
• Scalable manufacturing – Complex, multi-step production with low margins for error.

Extensive optimization using sophisticated analytics, genetic engineering and in vivo models is required to successfully overcome these challenges.

What are some examples of approved ADCs?

Several ADCs have received FDA approval for cancer treatment:

Dozens more ADCs are currently in clinical trials, and this technology is expected to expand further as an oncology treatment option.

What is the future outlook for ADCs?

ADCs are an emerging and promising class of targeted cancer therapies. Some trends for the future include:

• New ADCs targeting novel antigens beyond initial proofs-of-concept.
• Novel payloads with different mechanisms of action.
• Combination therapies, e.g. ADC + checkpoint inhibitor immunotherapy.
• ADCs for solid tumors, which present distinct challenges.
• Improved analytical methods and sophisticated computational models to accelerate ADC design.
• Next-generation ADCs with optimized pharmacokinetics, bystander killing ability, and enhanced tumor penetration.
• ADCs for non-oncology indications like autoimmune diseases.

In summary, ADCs are an enabling targeted therapy platform that is poised for further innovation and clinical impact, especially with new developments in antibody engineering, linker/cytotoxin technologies, and combination regimens.

References

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