Biocompare.com: Addressing Antibody-Drug Conjugate Development Challenges

Abzena’s Scientific Leader and Senior Vice President, Petra Dieterich Ph.D., features in a new article on Biocompare.

As part of the articles ‘Addressing Antibody-Drug Conjugate Development Challenges’ feature, Petra provided her thoughts on how ADC products still face existential issues like off-target toxicity, tumor heterogeneity, and unpredictable pharmacokinetics (PK).

“Drug developers are investigating several alternative formats to address these shortcomings,” Dieterich says, “including dual payload ADCs, bispecific ADCs and proteolytically activated antibody prodrugs (probodies).” Probodies mitigate “on-target, off-tumor” side effects from ADCs targeting receptors on both cancer and healthy cells by only releasing the drug inside the tumor.

Another potential fix for ADC toxicity are bispecific ADCs, which, as their name suggests, carry a cytotoxic payload but target two receptors simultaneously. Bispecific ADCs promise enhanced binding affinity, rapid internalization, and therefore higher potency.

“One thing to watch out for with bispecific ADCs is that target expression ratios on tumor cells can vary between tumors and between patients,” Dieterich tells Biocompare. “This can complicate the selection of targets, and requires the careful selection of epitopes and binding modes, and a greater understanding the drugs’ underlying biology.”

Rounding out other drug-antibody combinatorial possibilities are dual-drug ADCs, which seek to overcome tumor resistance to individual cytotoxic payloads by providing a one-two punch through a single dosing regime.

“Dual response may also be accompanied by additive or synergistic toxicities,” Dieterich explains, “so payloads need to be carefully selected based on their mechanism of action to achieve optimal therapeutic outcomes.” These efforts are still in the early stages of exploration.

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Abstract

Combining cancer cell-seeking antibodies with tumor-killing drugs or radionuclides is an old idea whose current embodiment, antibody-drug conjugates (ADCs), results from several generations of improvements leading from murine or chimeric antibodies unstably linked to poorly characterized payloads, to fully humanized antibodies, site-specific conjugation, and precisely calculated drug-antibody combinations…

Read the full article on Biocompare.

Bioconjugates, ADCs & Chemistry