The State-of-the-Art for Optimising ADCs

Chris Martin Co-Founder and Director, ADC Therapeutics

In this, presentation, Chris Martin, co-founder and director at ADC Therapeutics, SA, aimed to determine which viable methodologies work to optimize ADCs. He illustrated the many considerations and factors that help to determine the type of conjugate to use in patients. Martin also highlighted the number of ADCs that have gained FDA approvals, signifying the tremendous momentum in this space.

Increasing Therapeutics Index Through Targeted Toxin Delivery

Some key takeaways focused on viable methods to expand the therapeutic index. The discussion helped identify avenues to raise the dosage level administered to the cancer cell without further impacting patient health. Consideration in this area is needed because toxins administered at higher doses are notably more troublesome for patients to tolerate.

Managing Hydrophilic Toxins

Most toxins are hydrophilic and tend to present challenges such as off-target toxicity, and problems with manufacturability, particularly aggregation. Misfolded protein sometimes presents hydrophobic residues encouraging protein aggregation through hydrophobic interactions. Often, these interactions can result in the formation of soluble aggregates (oligomers). Suggestions for successfully managing hydrophilic antibodies included possibly engineering it out of the toxin as much as possible.

MOA to achieve Cell Kill (IO, Bystander)

The mechanism of apoptosis to achieve cell death may depend upon the tumor type. In the example of heterogenous expression of the target, a bystander kill would be ideal. However, you don’t always want bystander kill because it can sometimes result in systemic release of the toxin. The recommendation was to select immunogenic cell types such as PPD cells.

Conjugation Chemistry

Site-specific conjugation technologies tend to be favorable because they are simple and facilitate the production of homogeneous antibody–drug conjugates (ADCs). However, current site-specific conjugation methods can only attach one type of drug to a single antibody.Emerging technology features dual-site-specific conjugation methods enabling two modes of cell death. Both conjugation methodologies are complimentary, but dual-site conjugation is still in developmental stages and may not be viable.For the protein itself the goal is to reduce nonspecific uptake as much as possible. ADCs tend to have disturbances of the charge distribution, which, if extreme can cause considerable amounts of uptake resulting in restricted expression of the target protein.Suggestions on how to reduce non-specific uptake included:

Improve the tumor- specific binding of the antibodies.

Using alternative scaffolds such as peptides may provide a way of improving tumor penetration and reducing half-life.

Considerations for Optimizing the Whole ADC

Martin explained that understanding the tumor type, the nature of the disease, and the desired level of expression is helpful when considering which toxin to use. For example, highly potent toxins may present more advantages for specific protein targets. In contrast, using a toxin known for lower potential expression may be more suitable for hematological-based tumors and allow for a longer half-life and high exposure. Linker selection also plays a role. He said that in cases when the bystander kill effect isn't appropriate, substituting with a non-cleaving linker may assist the desired result.

Tolerability Considerations: Factors that Drive the Therapeutic Index

Though there are many more classes of toxins, four main toxins were noted and paired with the most reported adverse effects.

Pyrrolobenzodiazepine (PBD): Liver enzymes, rash, oedema

Auristatins: – peripheral neuropathy

Maytansine: ocular toxicity

Calicheamicin: veno-occlusive disease

Additionally, some common target cell protein toxicities related to cell expression include:

HER2: pleural effusion

CD22: neutropenia, (;can be acute and long-lasting)

BCMA: ocular toxicity

Advantages of PBD-based ADC approach

PBD-based ADC approaches offer a unique mechanism of action and work to maintain activity in patients who have become resistant or refractory to previous therapies. Because PBDs are very potent with picomolar IC50, they only require a drug-to-antibody ratio (DAR) of 2. They also feature a bystander effect with immunogenic cell death and cause DNA cross-linking. The result is minimal DNA distortion and the avoidance of DNA repair (excising and mismatch).Martin covered some special considerations when using PBD approaches:

Cancer cell protein targets must be more expressed on tumors rather than at healthy tissue.

Healthy tissue expression can be widespread at low levels, but not focused on sensitive organs such as lung, brain, or kidneys.

Clinical development must take into consideration the persistent cross-links.

Case Study Comparison of MEDI376 vs. ADCT-212

Martin shared a case study using ADCT-212 -a second generation, new and improved PSMA-targeted clinical candidate ADC, which offers expanded benefits over its predecessor:

Low Hydrophobicity

Good single dose in vivo efficacy in CWR22 and LNCAP xenograft models.

Excellent stability and good half-life in rats and cyno

Conclusion

Martin’s talk highlighted the various tools and advancements facilitating the current and future progress of ADC development. He emphasized his hope for more holistic approaches towards experimentation and responsible negotiation of model translation from en-Vivo-to en-Vitro-to-human. More exciting, the landscape for future innovation is exponential and aims to solve the many unknowns related to site-specific conjugation selection.