Insight Report

21/08/2024, 11:18:21

Objective
what is pathways in ADC research

Summary 1
### Pathways in Antibody-Drug Conjugate (ADC) Research

Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapies that
combine the specificity of monoclonal antibodies with the potent cytotoxic effects of
chemotherapeutic agents. The development and optimization of ADCs involve understanding
various biological pathways and mechanisms to enhance their efficacy and safety.

#### Background

ADCs are designed to selectively deliver cytotoxic drugs to cancer cells, thereby minimizing
systemic toxicity. They consist of three main components: a monoclonal antibody specific to a
tumor-associated antigen, a cytotoxic drug (payload), and a linker that connects the drug to the
antibody. The efficacy of ADCs depends on the stability of the linker in circulation, the specificity
and internalization of the antibody, and the potency of the cytotoxic drug.

#### Mechanistic Pathways and Targets

**1. HER2 Pathway:**

HER2 is a well-known target in breast and gastric cancers. HER2-targeted ADCs, such as
trastuzumab deruxtecan (DS-8201a), have shown significant efficacy. According to a study in
*Xenobiotica*, DS-8201a exhibits a stable linker in circulation and rapid clearance of the cytotoxic
drug upon release, resulting in low systemic exposure and minimal tissue-specific retention. This
ADC has demonstrated potent antitumor activity in HER2-positive cancers, including those with
low HER2 expression.

**2. WNT Signaling Pathway:**

The WNT signaling pathway is crucial in cancer stem cell (CSC) survival and tumor progression.
Aberrant WNT signaling is implicated in various cancers, including breast, colorectal, and lung
cancers. Targeting this pathway with ADCs, such as anti-PTK7 ADCs, has shown promise.
According to *Science Translational Medicine*, a PTK7-targeted ADC reduced tumor-initiating
cells (TICs) and induced sustained tumor regressions in preclinical models of triple-negative breast
cancer, ovarian cancer, and non-small cell lung cancer.
**3. cGAS-STING Pathway:**
The cGAS-STING pathway is essential for immune defense against tumors. ADCs targeting this
pathway can enhance antitumor immunity. A study in the *Proceedings of the National Academy of
Sciences* demonstrated that a STING agonist conjugated to a tumor-targeting antibody promoted
innate and adaptive immune responses, including activation of dendritic cells and T cells, and
showed synergistic effects with anti-PD-L1 antibodies.

**4. PI3K/Akt/mTOR Pathway:**

This pathway is frequently altered in cancers and is associated with cell proliferation and survival.
HER2-positive breast cancers often exhibit alterations in the PI3K/Akt/mTOR pathway. Targeting
this pathway with ADCs can enhance therapeutic efficacy. For instance, HER2-targeted ADCs like
trastuzumab deruxtecan have shown activity in tumors with PI3K pathway alterations, as noted in
*Breast (Edinburgh, Scotland)*.

**5. FGFR Pathway:**

The FGFR pathway is involved in cell growth and angiogenesis. FGFR inhibitors are being
explored in various cancers, including cholangiocarcinoma. Targeting FGFR with ADCs could
provide a precision medicine approach for cancers with FGFR alterations, as discussed in
*Seminars in Liver Disease*.

#### Clinical and Translational Insights

**1. Resistance Mechanisms:**

Resistance to ADCs can arise through various mechanisms, including antigen loss, drug efflux, and
alterations in the targeted pathway. Understanding these mechanisms is crucial for developing
next-generation ADCs and combination therapies. For example, resistance to HER2-targeted
therapies in gastric cancer involves multiple mechanisms, and novel ADCs are being developed to
overcome this resistance, as highlighted in *Biochimica et Biophysica Acta*.

**2. Combination Therapies:**

Combining ADCs with other therapeutic modalities, such as immune checkpoint inhibitors, can
enhance antitumor efficacy. For instance, combining HER2-targeted ADCs with PD-1/PD-L1
inhibitors has shown promise in preclinical models, as noted in *Cell Death & Disease*.

**3. Biomarker Development:**

Identifying biomarkers for patient selection and response monitoring is essential for the success of
ADC therapies. Multiomics approaches, including genomics, transcriptomics, and proteomics, are
being utilized to identify predictive biomarkers and optimize ADC treatment strategies, as discussed
in *Nature Genetics*.

### Conclusion

ADCs represent a sophisticated approach to cancer therapy, leveraging the specificity of antibodies
and the potency of cytotoxic drugs. Understanding the underlying biological pathways and
mechanisms is crucial for the development and optimization of ADCs. Ongoing research continues
to explore new targets, improve drug design, and develop combination strategies to enhance the
efficacy and safety of ADCs in cancer treatment.

Citations 1
1)
HER2-targeted therapies in gastric cancer.
Zhu Y, Zhu X, Wei X, Tang C, Zhang W,
Biochimica et biophysica acta. Reviews on cancer 1876 1
Aug
Link: https://www.ncbi.nlm.nih.gov/pubmed/33894300

2)
ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both
Wang J, Anderson MG, Oleksijew A, Vaidya KS, Boghaert ER, Tucker L, Zhang Q, Han EK,
Palma JP, Naumovski L, Reilly EB,
Clinical cancer research : an official journal of the American Association for Cancer Research 23 4
Feb 15 2017
Link: https://www.ncbi.nlm.nih.gov/pubmed/27573171

3)
Tumor-targeted delivery of a STING agonist improvescancer immunotherapy.
Wu YT, Fang Y, Wei Q, Shi H, Tan H, Deng Y, Zeng Z, Qiu J, Chen C, Sun L, Chen ZJ,
Proceedings of the National Academy of Sciences of the United States of America 119 49
Dec 06 2022
Link: https://www.ncbi.nlm.nih.gov/pubmed/36442099

4)
Follicular lymphoma: The long and winding road leading to your cure?
Gordon MJ, Smith MR, Nastoupil LJ,
Blood reviews 57
Jan
Link: https://www.ncbi.nlm.nih.gov/pubmed/35908982

5)
Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a
HER2-targeting antibody-drug conjugate, in cynomolgus monkeys.
Nagai Y, Oitate M, Shiozawa H, Ando O,
Xenobiotica; the fate of foreign compounds in biological systems 49 9
Sep
Link: https://www.ncbi.nlm.nih.gov/pubmed/30351177

6)
Dissecting the biological heterogeneity of HER2-positive breast cancer.
Schettini F, Prat A,
Breast (Edinburgh, Scotland) 59
Oct
Link: https://www.ncbi.nlm.nih.gov/pubmed/34392185

7)
MTX-13, a Novel PTK7-Directed Antibody-Drug Conjugate with Widened Therapeutic Index
Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors.
Kong C, Pu J, Zhao Q, Weng W, Ma L, Qian Y, Hu W, Meng X, Meng T,
Molecular cancer therapeutics 22 10
Oct 02 2023
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8)
Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell
carcinomas.
Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, Shukla SA, Guo G,
Brooks AN, Murray BA, Imielinski M, Hu X, Ling S, Akbani R, Rosenberg M, Cibulskis C,
Ramachandran A, Collisson EA, Kwiatkowski DJ, Lawrence MS, Weinstein JN, Verhaak RG,
Wu CJ, Hammerman PS, Cherniack AD, Getz G, Artyomov MN, Schreiber R, Govindan R,
Meyerson M,
Nature genetics 48 6
Jun
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Link: https://www.ncbi.nlm.nih.gov/pubmed/29531901

9)
Kynurenine pathway metabolism and neuroinflammatory disease.
Braidy N, Grant R,
Neural regeneration research 12 1
Jan
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10)
Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular
heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review).
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11)
Multiomics analyses of two Leonurus species illuminate leonurine biosynthesis and its evolution.
Li P, Yan MX, Liu P, Yang DJ, He ZK, Gao Y, Jiang Y, Kong Y, Zhong X, Wu S, Yang J,
Wang HX, Huang YB, Wang L, Chen XY, Hu YH, Zhao Q, Xu P,
Molecular plant 17 1
Jan 01 2024
Link: https://www.ncbi.nlm.nih.gov/pubmed/37950440
Link: https://www.ncbi.nlm.nih.gov/pubmed/38102830

12)
A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained
tumor regressions.
Damelin M, Bankovich A, Bernstein J, Lucas J, Chen L, Williams S, Park A, Aguilar J,
Ernstoff E, Charati M, Dushin R, Aujay M, Lee C, Ramoth H, Milton M, Hampl J, Lazetic S,
Pulito V, Rosfjord E, Sun Y, King L, Barletta F, Betts A, Guffroy M, Falahatpisheh H,
O'Donnell CJ, Stull R, Pysz M, Escarpe P, Liu D, Foord O, Gerber HP, Sapra P, Dylla SJ,
Science translational medicine 9 372
Jan 11 2017
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Link: https://www.ncbi.nlm.nih.gov/pubmed/29285495

13)
A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive
colon cancer by triggering the cGAS-STING pathway.
Wu X, Xu L, Li X, Zhou Y, Han X, Zhang W, Wang W, Guo W, Liu W, Xu Q, Gu Y,
Cell death & disease 14 8
Aug 24 2023
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14)
Synergistic Approach of Antibody-Photosensitizer Conjugate Independent of KRAS-Mutation and
Its Downstream Blockade Pathway in Colorectal Cancer.
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15)
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Hypotheses And Experimental Designs 1

1)
Hypothesis: HER2-targeted ADCs enhance therapeutic efficacy in HER2-positive cancers by
activating the PI3K/Akt/mTOR pathway, leading to increased cell proliferation and survival in
response to cytotoxic drug release.

2)
Hypothesis: The efficacy of anti-PTK7 ADCs in reducing tumor-initiating cells (TICs) in
triple-negative breast cancer is mediated through the inhibition of the WNT signaling pathway,
resulting in decreased CSC survival and tumor progression.

3)
Hypothesis: ADCs that target the cGAS-STING pathway enhance antitumor immunity by
promoting dendritic cell activation and T cell responses, which in turn leads to increased tumor cell
apoptosis and improved therapeutic outcomes.

4)
Hypothesis: FGFR-targeted ADCs improve clinical outcomes in cholangiocarcinoma by inhibiting
angiogenesis and cell growth through the FGFR signaling pathway, thereby reducing tumor
vascularization and enhancing drug delivery.

5)
Hypothesis: Resistance to HER2-targeted ADCs in gastric cancer is mediated by alterations in the
PI3K/Akt/mTOR pathway, which leads to increased drug efflux and antigen loss, suggesting that
combination therapies targeting this pathway may overcome resistance.