How Can Broadening Our Knowledge in Bioconjugate Design and Development Help Develop Better Medicines to Treat Oncology and Beyond?

Antibody-drug conjugates (ADCs) are at the forefront of targeted cancer therapy. They combine the precision of monoclonal antibodies (mAbs) with the potency of cytotoxic drugs to destroy cancer cells, without harming healthy tissue.

ADCs provide a wide therapeutic index — the range of drug dosages that can be administered without toxic side effects — of cytotoxic drugs by selectively delivering them to cells expressing specific antigens targeted by the mAbs. The efficacy of ADCs depends on antibody-specific, linker-specific and payload-specific factors interacting with the tumor and its microenvironment.

At least 13 ADCs have been approved by the US Food and Drug Administration (FDA) to treat a wide range of cancers cancers, including breast cancer, B-cell lymphoma, urothelial cancers and more, and there is an acceleration ADC entering Phase III clinical trials.

In a one-on-one with Xtalks, Dr. Petra Dieterich, Senior Vice President and Scientific Leader at Abzena, shared her comprehensive insights into the sophisticated world of ADCs and their evolving role in cancer treatment. Dr. Dieterich has a PhD in synthetic organic chemistry, an MBA from Imperial College London and a wealth of experience in drug development and chemistry, manufacturing and control (CMC) activities.

Abzena is a leader in bioconjugation and ADC development. They excel in the design and synthesis of complex small molecule, high potent chemistry and payload-linker constructs, supporting the rapid generation of structure-activity relationships (SAR) to identify the most suitable structures for specific ADC profiles.

ADCs Are Complicated Molecules

The design of an ADC requires careful consideration of three components — an antibody targeting a specific antigen on cancer cells, a cytotoxic drug (payload) and a linker connecting the two — to ensure specificity, efficacy and safety. Dr. Dieterich elaborated on the critical aspects of each component: “There’s the protein part, a small molecule and then there’s the linker part in the middle.” Upon binding to the target antigen on the tumor cell surface, the ADC is internalized, and the linker is cleaved, releasing the cytotoxic payload to induce cell death.

For the antibody component, the specificity of tumor cells is paramount. “We want to be targeting receptors that are specific to tumor cells. We want our antibody to have a long half-life in circulation and we want it to be retained in the circulation,” she explained. This targeting ensures the antibody can effectively deliver the toxic payload to the cancer cells without affecting normal cells.

Dr. Dieterich emphasized the importance of the payload’s chemical properties and its mechanism of action. The payload itself needs to be exceptionally toxic and potent. “We have to have a very highly potent payload. We want our payloads to be hydrophobic enough. If there is an opportunity to elucidate the bystander effect [where a cell responds to an event in the same way as the adjacent cell undergoing the event], it can diffuse into neighboring cancer cells and kill those for us as well,” said Dr. Dieterich.

The linker — cleavable or non-cleavable — that connects the antibody to the payload is equally vital, affecting the stability and release of the payload: “The chemistry that we use really defines the structure of our final ADC and how the loading of that antibody-drug ratio looks,” said Dr. Dieterich. Linkers need to be stable in blood circulation to ensure that there isn’t any shedding of the payload, risking toxicity. It is important to demonstrate that the ADC is safe and effective at killing target cells to ensure a successful regulatory submission.

Current Challenges in ADC Development

ADC development, while promising, is not without its challenges. Dr. Dieterich identified two primary hurdles: drug resistance and adverse-events. She uses the case of Enhertu (trastuzumab deruxtecan), a leading ADC for treating metastatic breast cancer, to illustrate these issues. “Enhertu’s the poster child amongst ADCs right now, it’s got pan-tumor potential and it’s really been extremely successful in combating breast cancer. Metastatic breast cancer response rates in clinical trials are up to 75 percent, but even there we’re seeing some significant issues with interstitial lung disease in about nine percent of patients,” she stated.

Enhertu is a HER2 (human epidermal growth factor receptor 2)-directed ADC that targets HER2-expressing cancer cells. It combines an HER2 monoclonal antibody with a potent topoisomerase I inhibitor (exatecan derivative or DXd) via a cleavable linker. Data from AstraZeneca’s DESTINY-Breast03 and DESTINY-Breast07 trials highlight Enhertu’s potential as a first line standard of care for HER2-positive metastatic breast cancer.

Dr. Dieterich suggested that increased adverse effects can often be attributed to drug resistance mechanisms driven by tumor heterogeneity, which changes how drugs work against the tumor. These changes in the tumor environment help the tumor resist treatment by modifying gene activity, avoiding immune detection and supporting survival pathways. As the tumor grows and adapts, its surrounding environment becomes better at resisting the effects of treatment, creating major challenges for effectively targeting the cancer.

“Drug resistance is really the root of this, and it’s brought about by tumor heterogeneity, and the different responses to treatment are caused by the different strains in the cancer having different responses to the ADCs. That leads to resistant strains and then [the] treatment stops working,” she said. Dr. Dieterich alluded to the initial discontinuation of the drug Mylotarg (gemtuzumab ozogamicin) due to its high fatal toxicity rate as compared to chemotherapy. However, it has since been authorized for use under different treatment regimens and with boxed warnings.

Exploring Bioconjugate Design for Targeted Cancer Therapy

Dr. Dieterich detailed the sophisticated strategies used to enhance the specificity of ADCs in targeting cancer cells while mitigating damage to healthy tissues. “We want to look for a receptor that’s unique to that cell and less expressed in a healthy cell so that healthy cells still stay healthy,” she explained. This focus ensures that the ADC can deliver its cytotoxic payload directly to the cancer cells without affecting normal tissues.

Many receptors found on cancer cells are also present on normal cells, though often at lower levels. This overlap can lead to what is known as “on-target off-tumor effects,” where the ADC affects non-cancerous cells, leading to potential toxicity.

Innovative formats like bispecific antibodies (bsAbs) and probody drug conjugates (PDCs) use molecular engineering to target multiple pathways or deliver cytotoxic drugs directly to cancer cells.

PDCs are modified ADCs where the antibody’s antigen-binding site is masked, preventing it from binding to receptors until it reaches the tumor microenvironment. This design helps minimize harmful interactions with healthy cells. “So, we would mask the antigen binding site, or we could also alter the confirmation so that we don’t get binding straight away to those receptors,” said Dr. Dieterich.

CytomX Therapeutics is at the helm of this next-generation targeted antibody therapeutics. They recently shared positive anti-cancer data from their ongoing Phase Ia dose escalation study with Amgen for the investigational, masked, conditionally activated probody T-cell engager, CX-904, that targets the epidermal growth factor receptor (EGFR) on cancer cells and the CD3 receptor on T cells within the tumor microenvironment.

BsAbs, on the other hand, target two different antigens (or two epitopes of the same antigen) on cancer cells. This dual targeting could potentially enhance the ADC’s ability to selectively bind and destroy cancer cells, reducing the risk of affecting normal cells. BsAbs, such as Genentech’s Columvi (glofitamab-gxbm), have been primarily developed for cancer treatment, particularly breast cancer.

Dr. Dieterich notes the potential of this approach but also cautions about the risks, such as agonistic effects that might lead to incorrect targeting.

Key Takeaways from ADC Development

The expertise gained from ADC development is not confined to cancer therapies alone. It is also being applied to other therapeutic areas such as antibody-oligo conjugates (AOCs). Dr. Dieterich discussed the potential of applying ADC techniques to AOCs, which use oligonucleotides to interfere with mRNA and, thus, protein production.

“Over the years, we’ve built a plethora of techniques for conjugating the different targeting proteins with a range of different payloads. We can have a standard monoclonal antibody with a high potent or MMAE (monomethyl auristatin E); that’s a favorite high potent. And we can vary that and apply lots of different design options,” elaborated Dr. Dieterich on the versatility of these techniques.

Oligonucleotides such as antisense and small-interfering RNAs, are crafted using advanced chemical processes. They act by modifying protein expression, offering new treatments for rare diseases. Despite their potential, oligonucleotides present challenges in bioavailability due to their large, hydrophobic and negatively charged nature. Dr. Dieterich advocated the need for systemic delivery approaches, such as bioconjugation with a targeting protein. Using ADC techniques, such as creating bifunctional linkers can facilitate conjugation. Providing more treatments options that can treat higher volume diseases.

Linkers can be customized for their hydrophobicity through the addition of polyethylene glycol (PEG) or carbohydrates. This modification not only improves the solubility and stability of the drug but also extends its circulation half-life, which is crucial for therapeutic efficacy.

Dr. Dieterich underscored the importance of these innovations in developing treatments that are more effective and easier for patients to manage, demonstrating a keen application of learned chemistry to address new challenges in drug development.

The conversation with Dr. Dieterich highlighted the dynamic nature of this field. ADCs have emerged as powerful tools in the fight against cancer. Despite their transformative potential, several challenges must be overcome to maximize their therapeutic efficacy and safety. As the field continues to evolve, the prospects of ADCs are also expanding, promising more targeted and effective treatments across a broader range of diseases.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.