Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

Lucas, Andrew T.; Moody, Amber S.; Schorzman, Allison N.; Zamboni, William C.

doi:10.3390/antib10030030

Cited by 19 publications

(14 citation statements)

References 255 publications

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“…Poor tissue penetration of ADCs is a major limitation to their efficacy and has hampered wider clinical success of ADCs 11 , 26 , 34 , 36 , 37 . Higher antibody doses, whether via lower DAR 37 , 39 , 40 , more tolerable payloads 41 , or adding carrier doses 11 , 26 , 27 , 42 can improve the efficacy while lowering target-mediated uptake in healthy tissue to improve the therapeutic window. However, the lower (effective) DAR can also reduce efficacy in lower expression models 11 , 43 , 44 .…”

Section: Discussionmentioning

confidence: 99%

Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting

Evans

Thurber

2022

Sci Rep

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Antibody-Drug Conjugates (ADCs) have rapidly expanded in the clinic, with 7 new approvals in 3 years. For solid tumors, high doses of ADCs improve tissue penetration and efficacy. These doses are enabled by lower drug-to-antibody ratios and/or co-administration of unconjugated antibody carrier doses to avoid payload toxicity. While effective for highly expressed targets, these strategies may not maintain efficacy with lower target expression. To address this issue, a carrier dose that adjusts binding in situ according to cellular expression was designed using computational modeling. Previous studies demonstrated that coadministration of unconjugated antibody with the corresponding ADC at an 8:1 ratio improves ADCs efficacy in high HER2 expressing tumors. By designing a High Avidity, Low Affinity (HALA) carrier antibody, ADC binding is partially blocked in high expression cells, improving tissue penetration. In contrast, the HALA antibody cannot compete with the ADC in low expressing cells, allowing ADC binding to the majority of receptors. Thus, the amount of competition from the carrier dose automatically adjusts to expression levels, allowing tailored competition between different patients/metastases. The computational model highlights two dimensionless numbers, the Thiele modulus and a newly defined competition number, to design an optimal HALA antibody carrier dose for any target.

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Section: Discussionmentioning

confidence: 99%

Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting

Evans

Thurber

2022

Sci Rep

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“…ADCs are the most rapidly emerging monoclonal antibody-based cancer immunotherapy field, with significantly greater potency than naked antibodies [ 242 , 243 ]. This strategy employs a mAb attached to the cytotoxic payload via a chemical linker directed to a target cell surface antigen expressed on the cancer cells [ 244 , 245 , 246 ].…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

“…Typically, ADC contains three components: the monoclonal antibody (mAb), the linker, and the cytotoxic or cytostatic/cytotoxic drug. The mAb is an essential component of ADC that dictates specificity to the tumor cell, by binding to tumor antigens, acts as a precise carrier to transport the cytotoxic agents to the target cell without harming healthy cells that do not express the target antigen [ 242 , 243 , 245 , 246 , 247 , 248 ]. The second component of ADC is a linker.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

“…ADCs are complex structures that require careful consideration of their many components. The choice of a suitable target, the specificity of mAb, the cytotoxic payload, and the method by which the antibody is coupled to the payload are all important factors that may determine the safety and efficacy of ADCs [ 243 , 245 , 250 , 252 , 253 ]. The specificity of the antibody to the target antigen limits systemic exposure and toxicity [ 245 ].…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

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Emerging Trends in Immunotherapy for Cancer

et al. 2022

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Recent advances in cancer immunology have enabled the discovery of promising immunotherapies for various malignancies that have shifted the cancer treatment paradigm. The innovative research and clinical advancements of immunotherapy approaches have prolonged the survival of patients with relapsed or refractory metastatic cancers. Since the U.S. FDA approved the first immune checkpoint inhibitor in 2011, the field of cancer immunotherapy has grown exponentially. Multiple therapeutic approaches or agents to manipulate different aspects of the immune system are currently in development. These include cancer vaccines, adoptive cell therapies (such as CAR-T or NK cell therapy), monoclonal antibodies, cytokine therapies, oncolytic viruses, and inhibitors targeting immune checkpoints that have demonstrated promising clinical efficacy. Multiple immunotherapeutic approaches have been approved for specific cancer treatments, while others are currently in preclinical and clinical trial stages. Given the success of immunotherapy, there has been a tremendous thrust to improve the clinical efficacy of various agents and strategies implemented so far. Here, we present a comprehensive overview of the development and clinical implementation of various immunotherapy approaches currently being used to treat cancer. We also highlight the latest developments, emerging trends, limitations, and future promises of cancer immunotherapy.

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“…Alongside the excitement in the field, we are seeing several strategies for antibody engineering designed to modulate the pharmacological properties of ADCs. Lucas and colleagues [ 7 ] provide a comprehensive overview of antibody engineering to alter the interaction of ADCs with the immune system, to influence pharmacokinetics, pharmacodynamics and the therapeutic index of ADCs. The authors highlight interesting engineering approaches which can be employed for the design of the next generation of ADCs.…”

mentioning

confidence: 99%