ADC combined therapy is anticipated to provide a new treatment option for individuals with lung cancer

Posted January 17, 2022 by beauty33

Antibody-drug conjugates (ADCs) are a type of targeted biological agent that a target-specific monoclonal antibody combines with a cytotoxic drug via a specific chemical linker.
Antibody-drug conjugates (ADCs) are a type of targeted biological agent that a target-specific monoclonal antibody combines with a cytotoxic drug via a specific chemical linker. The monoclonal antibody is used as a carrier to efficiently transport small molecule cytotoxic drug to target tumor cells.

Because lung cancer has the greatest incidence and fatality rate in the world, researchers have never ceased looking for ways of treatment. Lung cancer-related ADC treatments are becoming more commonly accessible, in addition to targeted therapies and immunotherapy. ADC drugs have been demonstrated to be effective in treating patients with resistant non-small cell lung cancer (NSCLC), with objective remission rates (ORRs) ranging from 20.3% to 39% in previous studies. However, many obstacles remain, including the toxic side effects during treatment, the lack of ideal predictive biomarkers, inadequate understanding of ADC drug resistance mechanisms at the moment, and the search for a reasonable ADC combination therapy strategy.

A rational ADC combination strategy can increase ADC activity, which may be achieved in four forms.

1. Increase ADC delivery to tumor tissue: Anti-angiogenic drugs, such as those targeting the VEGF signaling pathway, may improve ADC delivery to tumor tissue by promoting normalization of tumor blood vessels, or enhance the cytotoxic effects of ADC.
2. Modulation of antibody target protein expression and/or processes: Drugs that increase the expression of target antigens on the tumor cell surface may promote antibody-antigen binding. Alternatively, drugs that enhance antigen conversion or degradation may promote ADC uptake and payload cleavage and release, thereby enhancing cytotoxicity.
3. Enhance payload activity and/or synthetic killing: Other drugs that act synergistically through complementary mechanisms or synthetic killing may enhance payload activity.
4. Promote antitumor immunity: Immunotherapy has the potential to build on the antitumor immunity induced by ADCs, either by enhancing antibody-dependent cellular cytotoxicity or by enhancing cell-mediated tumor recognition and immune effector functions.

New advances in ADC combination therapy for NSCLC

1.Combination study of ADC and anti-angiogenic drugs
SAR408701, a DM4-binding ADC targeting carcinoembryonic antigen-associated cell adhesion molecule 5 (CEACAM5), showed good antitumor activity in advanced non-squamous NSCLC patients with high CEACAM5 expression who had previously received multiple lines of therapy in a dose-expansion cohort study of SAR408701 for non-squamous NSCLC (NCT02187848) at the 2020 ASCO Annual Meeting.

2.Irreversible pan-HER inhibitor enhances T-DM1 activity
To determine whether enhanced receptor internalization induced by combination treatment with neratinib and T-DM1 enhances anti-tumor efficacy, this preclinical study used neratinib, T-DM1, or combination treatment with ERBB2 amplification and mutation (S310F) in an identical lung patient tumor xenograft model (PDX). The results showed that while both T-DM1 and T-DM1 in combination with neratinib induced significant tumor regression, and the effects of combination therapy were more durable (although the activity observed with neratinib monotherapy was negligible).

3.Potential synergy between ADC and immune checkpoint inhibitor (ICI)
Trastuzumab Deruxtecan (T-Dxd) was shown to enhance anti-tumor immune function in a homozygous mouse model.

Several ADC combination therapy studies are currently underway, and more are projected to be used in the clinical treatment of NSCLC patients in the future.
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Last Updated January 17, 2022