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Luis A. Romero

@leoncologo

Oncólogo Clínico.🦀🧬💊 Vasallo insurrecto del emperador de todos los males. Cáncer, ciencia, libros, música, sarcasmo ...y una que otra opinión personal.
León, Guanajuato
Joined July 2022
53 Following
42 Followers
30 Posts
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오창명 Verified account @changmyung1981
🧬💣 Antibody–drug conjugates were designed as “magic bullets.” But a new 2026 JCI Review argues that the most successful ADCs are not really precision missiles—they are hybrid therapies combining targeted distribution with chemotherapy-like, spatially distributed killing. That distinction may explain why ADCs have transformed breast cancer treatment. ADC ≠ antibody + chemotherapy Instead: ANTIBODY determines where the drug preferentially travels LINKER determines where/when payload is released PAYLOAD determines what happens after release TUMOR MICROENVIRONMENT determines how far the effect spreads. Guo & Ellisen therefore propose a more nuanced view: ADCs are targeted primarily in BIODISTRIBUTION—not necessarily in CYTOTOXICITY. 207630.1-20260930212758-covered… That may be the key conceptual shift in this excellent review. 🎯 The original ADC model was simple Paul Ehrlich's “magic bullet” concept: ANTIBODY ↓ tumor antigen ↓ internalization ↓ lysosome ↓ payload release ↓ TARGET CELL DIES A conventional ADC contains: antibody linker cytotoxic payload. 207630.1-20260930212758-covered… But modern ADC biology is much messier—and more interesting. Today's effective ADCs can also act through: EXTRACELLULAR PAYLOAD RELEASE BYSTANDER KILLING Fc-MEDIATED IMMUNITY IMMUNOGENIC CELL DEATH TARGET-INDEPENDENT UPTAKE meaning an antigen-positive cell may function partly as a: LOCAL DRUG-DELIVERY HUB rather than the only cell destined to die. 207630.1-20260930212758-covered… 🔥 The clearest example: T-DM1 vs T-DXd Both target: HER2 and both use trastuzumab. Yet their clinical behavior is dramatically different. T-DM1 HER2 antibody noncleavable MCC linker DM1 tubulin inhibitor DAR ≈ 4 membrane-impermeable payload → essentially NO BYSTANDER EFFECT versus T-DXd HER2 antibody cathepsin-cleavable linker DXd TOP1 inhibitor DAR ≈ 8 membrane-permeable payload → STRONG BYSTANDER EFFECT. 207630.1-20260930212758-covered… 207630.1-20260930212758-covered… And the clinical difference is substantial. In DESTINY-Breast03: T-DXd PFS = 25.1 months versus T-DM1 = 7.2 months and in DESTINY-Breast05, 3-year invasive disease-free survival was: 92.4% vs 83.7%. 207630.1-20260930212758-covered… Same antibody. Same target. Very different drug. That tells us something fundamental: THE PAYLOAD–LINKER SYSTEM CAN MATTER AS MUCH AS THE ANTIBODY. 💥 BYSTANDER KILLING changed the meaning of “HER2-targeted” T-DM1 largely requires: HER2⁺ CELL → INTERNALIZATION → DEATH. But T-DXd can release membrane-permeable DXd that diffuses into neighboring: HER2-low or even HER2-negative cells. 207630.1-20260930212758-covered… This helps explain one of the biggest conceptual changes in breast oncology: HER2 is no longer merely an oncogenic driver. For an ADC, HER2 can also function as: A DELIVERY ADDRESS. That is why T-DXd works in: HER2-low and even HER2-ultralow breast cancer populations that would historically not have been considered candidates for HER2-targeted therapy. 207630.1-20260930212758-covered… 🧬 The same logic applies to TROP2 ADCs The FDA-approved breast cancer ADC landscape discussed in the review includes four major agents: T-DM1 → HER2 / DM1 T-DXd → HER2 / DXd Dato-DXd → TROP2 / DXd SG → TROP2 / SN-38. Three of these use: TOP1 INHIBITOR PAYLOADS and support bystander killing. 207630.1-20260930212758-covered… In metastatic TNBC, sacituzumab govitecan transformed treatment. In ASCENT: median PFS 5.6 vs 1.7 months median OS 12.1 vs 6.7 months versus chemotherapy. 207630.1-20260930212758-covered… The emergence of these drugs is particularly important because TNBC historically lacked strong target-selective therapeutic options. 🧪 LINKER chemistry may be the hidden pharmacology of ADCs Linkers determine: WHERE and WHEN the payload becomes pharmacologically active. Noncleavable linker: ADC → internalization → lysosomal degradation → payload Cleavable linker: ADC → protease / acidic pH / reducing environment → payload release and potentially: EXTRACELLULAR RELEASE. 207630.1-20260930212758-covered… This means ADC activity does not necessarily require every antibody molecule to enter a cancer cell. Extracellular proteases in the TME may cleave some linkers before internalization. For SG, acidic conditions can promote linker hydrolysis. Thus: TME BIOLOGY BECOMES PART OF ADC PHARMACOLOGY. ⚖️ More payload is NOT always better Another important concept is: DAR — drug-to-antibody ratio. Intuitively: higher DAR → more payload → better ADC. But biology disagrees. High DAR also causes: hydrophobicity ↑ aggregation ↑ clearance ↑ tolerability ↓. And the authors discuss the fascinating: “SATURATION FRONT” phenomenon. High-payload/high-affinity ADCs can bind rapidly to cells around tumor vessels. That creates: PERIVASCULAR SATURATION and prevents deeper tumor penetration. 207630.1-20260930212758-covered… So paradoxically: MORE DRUG PER ANTIBODY can sometimes mean LESS EFFECTIVE TUMOR DISTRIBUTION. 🤯 And perhaps <1% reaches the tumor One particularly sobering observation in the review: on-tumor ADC distribution is typically <1% of the administered dose. 207630.1-20260930212758-covered… That alone challenges the simplistic “precision missile” metaphor. Most ADC molecules do not end up neatly delivering their payload exclusively to antigen-positive cancer cells. This also helps explain why: OFF-TUMOR TOXICITY remains central to ADC pharmacology. ⚠️ Toxicity is often NOT caused by target expression Consider T-DXd. Its most concerning toxicity is: INTERSTITIAL LUNG DISEASE / PNEUMONITIS reported in up to ~15% of patients in the literature reviewed here. Yet the review emphasizes that this appears largely: TARGET-INDEPENDENT rather than simply HER2-mediated toxicity in lung epithelium. Preclinical work points toward ADC uptake by: ALVEOLAR MACROPHAGES. 207630.1-20260930212758-covered… Likewise, T-DM1-associated thrombocytopenia can involve: FcγRIIa-mediated uptake or macropinocytosis by megakaryocytes. 207630.1-20260930212758-covered… So ADC toxicity depends on: TARGET LINKER STABILITY PAYLOAD Fc BIOLOGY NONSPECIFIC CELLULAR UPTAKE. 🧠 Then comes the major biomarker problem We currently select ADCs largely using: TARGET EXPRESSION. But target abundance is an incomplete biomarker. ADC efficacy can depend on: antigen abundance antigen heterogeneity internalization receptor recycling lysosomal processing linker cleavage payload sensitivity efflux transporters apoptosis competence tumor penetration. The diagram in Figure 2, page 5 captures this beautifully. 207630.1-20260930212758-covered… So: HER2 IHC ≠ COMPLETE ADC BIOMARKER and TROP2 IHC ≠ COMPLETE ADC BIOMARKER. 🔄 Worse: the target itself changes during treatment HER2 is not static. Treatment pressure can shift tumors between: HER2-positive ↔ HER2-low ↔ HER2-zero. 207630.1-20260930212758-covered… After T-DXd progression: 49% of paired patient samples reportedly showed HER2 downregulation, and more than half of those showed: COMPLETE HER2 LOSS. 207630.1-20260930212758-covered… Resistance can also occur without antigen loss through HER2 binding-site mutations such as: V597M P593R which preserve surface expression but reduce trastuzumab binding. So a biopsy saying: “HER2 PRESENT” does not necessarily mean: “T-DXd CAN STILL BIND EFFECTIVELY.” 💣 PAYLOAD resistance may be equally important A tumor can preserve the ADC target but become resistant to its warhead. Examples include: lysosomal dysfunction SLC46A3 loss caveolin-mediated trafficking changes STAT3 activation PLK1 activation ABCC1 drug efflux. 207630.1-20260930212758-covered… And perhaps most strikingly: TOP1 MUTATIONS were detected in: 12.9% of patients progressing after TOP1i ADCs versus 0.7% in ADC-naive breast cancer. 207630.1-20260930212758-covered… Patients harboring these mutations had dramatically shorter responses to subsequent TOP1i ADCs: 52 vs 455 DAYS. 207630.1-20260930212758-covered… That provides a mechanistic explanation for: ADC CROSS-RESISTANCE. 🔁 This makes ADC SEQUENCING a major clinical problem Suppose a patient progresses on: T-DXd HER2 → DXd Should we switch to: SG TROP2 → SN-38? The antibody target changes. But both payloads inhibit: TOP1. Therefore: TARGET SWITCH ≠ MECHANISM SWITCH. Real-world analyses suggest cross-resistance is particularly problematic when sequential ADCs share payload mechanisms. 207630.1-20260930212758-covered… One multicenter study cited in the review found approximately: different payload class → ORR 22.6% same payload class → ORR 5.3% although PFS remained similar and these data remain retrospective. 207630.1-20260930212758-covered… This suggests future ADC sequencing may require something analogous to antimicrobial resistance testing: WHAT TARGET REMAINS? WHAT PAYLOAD IS THE TUMOR STILL SENSITIVE TO? 🧬 A future ADC biopsy may therefore need MULTI-DIMENSIONAL profiling Not simply: HER2 = 1+ but perhaps: HER2 abundance + spatial heterogeneity TROP2 abundance binding-site mutation status TOP1 status ABCC1 expression lysosomal function SLC46A3 DNA repair state TME penetration immune context. The review specifically highlights: quantitative immunofluorescence spatial antigen mapping and AI-assisted digital pathology as emerging approaches beyond conventional categorical IHC. 207630.1-20260930212758-covered… 🛡️ ADCs may also function as IMMUNOTHERAPY TOP1 inhibitor payloads can trigger: IMMUNOGENIC CELL DEATH including: calreticulin exposure HMGB1 release ATP release leading to: dendritic-cell activation → antigen presentation → T-cell priming. 207630.1-20260930212758-covered… The antibody component can additionally promote: ADCC via NK cells and ADCP via macrophages. Figure 3 on page 6 nicely illustrates how bystander killing, extracellular payload release, ADCC, ADCP, immunogenic cell death, stromal barriers and abnormal vasculature all interact within the TME. 207630.1-20260930212758-covered… So ADCs are potentially: TARGETED DELIVERY CHEMOTHERAPY IMMUNE MODULATION. 🔥 ADC + ICI combinations are already testing this idea In first-line PD-L1-positive advanced TNBC: SG + pembrolizumab improved PFS over chemotherapy + pembrolizumab in ASCENT-04. And in BEGONIA: Dato-DXd + durvalumab produced approximately: 80% ORR regardless of PD-L1 expression. 207630.1-20260930212758-covered… But the story is not universally positive. T-DXd + nivolumab has so far produced response rates broadly comparable with historical T-DXd monotherapy. And DAISY biomarker analyses did not show a clear increase in granzyme-B⁺ CD8 T cells during T-DXd therapy. 207630.1-20260930212758-covered… So: ICD IN MICE ≠ GUARANTEED ICI SYNERGY IN HUMANS. That translational distinction is important. 🧬 Another rational combination: ADC + PARP inhibition TOP1 inhibitors trap: TOP1 cleavage complexes on DNA. PARP inhibition can further prevent repair of this damage. Thus: TOP1i ADC PARPi = DNA DAMAGE AMPLIFICATION. 207630.1-20260930212758-covered… The interesting pharmacological idea is that ADC delivery may create a larger: TUMOR : NORMAL PAYLOAD GRADIENT allowing sequential ADC/PARPi dosing that might be too toxic if both drugs were delivered systemically. 🚀 But the FUTURE of ADCs may look nothing like chemotherapy This is perhaps the most exciting part of the review. The next generation expands along: THREE AXES 1️⃣ NEW TARGETS Beyond HER2 and TROP2: HER3 Nectin-4 mesothelin FOLR1 B7-H3 B7-H4 Claudin 18.2 LIV1 ROR1/ROR2 tissue factor. And even: CANCER-ASSOCIATED FIBROBLASTS or ENDOTHELIAL CELLS can become ADC targets. 207630.1-20260930212758-covered… That represents another conceptual shift: THE ANTIBODY DOESN'T EVEN HAVE TO TARGET THE CANCER CELL. A stromal target can function as an anchor for local payload release. 2️⃣ NEW PAYLOADS Future ADC-like conjugates may carry: 🧬 siRNA ♻️ PROTACs 🧲 molecular glues 🛡️ STING agonists 🔥 TLR7/8 agonists ☢️ radionuclides 💡 photosensitizers ☠️ immunotoxins ✍️ α-amanitin. 207630.1-20260930212758-covered… Table 4 on page 10 shows just how far the field has moved beyond conventional cytotoxic payloads. 207630.1-20260930212758-covered… Perhaps eventually the term: ANTIBODY–DRUG CONJUGATE will become too narrow. These are increasingly: ANTIBODY-GUIDED MOLECULAR DELIVERY PLATFORMS. 3️⃣ SMARTER ANTIBODIES Next-generation engineering includes: biparatopic ADCs → two epitopes on one antigen bispecific ADCs → two different antigens dual-payload ADCs → two different warheads probody ADCs → masked until activated in the TME Fc engineering → tune immunity / half-life
changmyung1981's tweet photo. 🧬💣 Antibody–drug conjugates were designed as “magic bullets.” But a new 2026 JCI Review argues that the most successful ADCs are not really precision missiles—they are hybrid therapies combining targeted distribution with chemotherapy-like, spatially distributed killing. That distinction may explain why ADCs have transformed breast cancer treatment. ADC ≠ antibody + chemotherapy Instead: ANTIBODY determines where the drug preferentially travels LINKER determines where/when payload is released PAYLOAD determines what happens after release TUMOR MICROENVIRONMENT determines how far the effect spreads. Guo & Ellisen therefore propose a more nuanced view: ADCs are targeted primarily in BIODISTRIBUTION—not necessarily in CYTOTOXICITY. 207630.1-20260930212758-covered… That may be the key conceptual shift in this excellent review. 🎯 The original ADC model was simple Paul Ehrlich's “magic bullet” concept: ANTIBODY ↓ tumor antigen ↓ internalization ↓ lysosome ↓ payload release ↓ TARGET CELL DIES A conventional ADC contains: antibody linker cytotoxic payload. 207630.1-20260930212758-covered… But modern ADC biology is much messier—and more interesting. Today's effective ADCs can also act through: EXTRACELLULAR PAYLOAD RELEASE BYSTANDER KILLING Fc-MEDIATED IMMUNITY IMMUNOGENIC CELL DEATH TARGET-INDEPENDENT UPTAKE meaning an antigen-positive cell may function partly as a: LOCAL DRUG-DELIVERY HUB rather than the only cell destined to die. 207630.1-20260930212758-covered… 🔥 The clearest example: T-DM1 vs T-DXd Both target: HER2 and both use trastuzumab. Yet their clinical behavior is dramatically different. T-DM1 HER2 antibody noncleavable MCC linker DM1 tubulin inhibitor DAR ≈ 4 membrane-impermeable payload → essentially NO BYSTANDER EFFECT versus T-DXd HER2 antibody cathepsin-cleavable linker DXd TOP1 inhibitor DAR ≈ 8 membrane-permeable payload → STRONG BYSTANDER EFFECT. 207630.1-20260930212758-covered… 207630.1-20260930212758-covered… And the clinical difference is substantial. In DESTINY-Breast03: T-DXd PFS = 25.1 months versus T-DM1 = 7.2 months and in DESTINY-Breast05, 3-year invasive disease-free survival was: 92.4% vs 83.7%. 207630.1-20260930212758-covered… Same antibody. Same target. Very different drug. That tells us something fundamental: THE PAYLOAD–LINKER SYSTEM CAN MATTER AS MUCH AS THE ANTIBODY. 💥 BYSTANDER KILLING changed the meaning of “HER2-targeted” T-DM1 largely requires: HER2⁺ CELL → INTERNALIZATION → DEATH. But T-DXd can release membrane-permeable DXd that diffuses into neighboring: HER2-low or even HER2-negative cells. 207630.1-20260930212758-covered… This helps explain one of the biggest conceptual changes in breast oncology: HER2 is no longer merely an oncogenic driver. For an ADC, HER2 can also function as: A DELIVERY ADDRESS. That is why T-DXd works in: HER2-low and even HER2-ultralow breast cancer populations that would historically not have been considered candidates for HER2-targeted therapy. 207630.1-20260930212758-covered… 🧬 The same logic applies to TROP2 ADCs The FDA-approved breast cancer ADC landscape discussed in the review includes four major agents: T-DM1 → HER2 / DM1 T-DXd → HER2 / DXd Dato-DXd → TROP2 / DXd SG → TROP2 / SN-38. Three of these use: TOP1 INHIBITOR PAYLOADS and support bystander killing. 207630.1-20260930212758-covered… In metastatic TNBC, sacituzumab govitecan transformed treatment. In ASCENT: median PFS 5.6 vs 1.7 months median OS 12.1 vs 6.7 months versus chemotherapy. 207630.1-20260930212758-covered… The emergence of these drugs is particularly important because TNBC historically lacked strong target-selective therapeutic options. 🧪 LINKER chemistry may be the hidden pharmacology of ADCs Linkers determine: WHERE and WHEN the payload becomes pharmacologically active. Noncleavable linker: ADC → internalization → lysosomal degradation → payload Cleavable linker: ADC → protease / acidic pH / reducing environment → payload release and potentially: EXTRACELLULAR RELEASE. 207630.1-20260930212758-covered… This means ADC activity does not necessarily require every antibody molecule to enter a cancer cell. Extracellular proteases in the TME may cleave some linkers before internalization. For SG, acidic conditions can promote linker hydrolysis. Thus: TME BIOLOGY BECOMES PART OF ADC PHARMACOLOGY. ⚖️ More payload is NOT always better Another important concept is: DAR — drug-to-antibody ratio. Intuitively: higher DAR → more payload → better ADC. But biology disagrees. High DAR also causes: hydrophobicity ↑ aggregation ↑ clearance ↑ tolerability ↓. And the authors discuss the fascinating: “SATURATION FRONT” phenomenon. High-payload/high-affinity ADCs can bind rapidly to cells around tumor vessels. That creates: PERIVASCULAR SATURATION and prevents deeper tumor penetration. 207630.1-20260930212758-covered… So paradoxically: MORE DRUG PER ANTIBODY can sometimes mean LESS EFFECTIVE TUMOR DISTRIBUTION. 🤯 And perhaps <1% reaches the tumor One particularly sobering observation in the review: on-tumor ADC distribution is typically <1% of the administered dose. 207630.1-20260930212758-covered… That alone challenges the simplistic “precision missile” metaphor. Most ADC molecules do not end up neatly delivering their payload exclusively to antigen-positive cancer cells. This also helps explain why: OFF-TUMOR TOXICITY remains central to ADC pharmacology. ⚠️ Toxicity is often NOT caused by target expression Consider T-DXd. Its most concerning toxicity is: INTERSTITIAL LUNG DISEASE / PNEUMONITIS reported in up to ~15% of patients in the literature reviewed here. Yet the review emphasizes that this appears largely: TARGET-INDEPENDENT rather than simply HER2-mediated toxicity in lung epithelium. Preclinical work points toward ADC uptake by: ALVEOLAR MACROPHAGES. 207630.1-20260930212758-covered… Likewise, T-DM1-associated thrombocytopenia can involve: FcγRIIa-mediated uptake or macropinocytosis by megakaryocytes. 207630.1-20260930212758-covered… So ADC toxicity depends on: TARGET LINKER STABILITY PAYLOAD Fc BIOLOGY NONSPECIFIC CELLULAR UPTAKE. 🧠 Then comes the major biomarker problem We currently select ADCs largely using: TARGET EXPRESSION. But target abundance is an incomplete biomarker. ADC efficacy can depend on: antigen abundance antigen heterogeneity internalization receptor recycling lysosomal processing linker cleavage payload sensitivity efflux transporters apoptosis competence tumor penetration. The diagram in Figure 2, page 5 captures this beautifully. 207630.1-20260930212758-covered… So: HER2 IHC ≠ COMPLETE ADC BIOMARKER and TROP2 IHC ≠ COMPLETE ADC BIOMARKER. 🔄 Worse: the target itself changes during treatment HER2 is not static. Treatment pressure can shift tumors between: HER2-positive ↔ HER2-low ↔ HER2-zero. 207630.1-20260930212758-covered… After T-DXd progression: 49% of paired patient samples reportedly showed HER2 downregulation, and more than half of those showed: COMPLETE HER2 LOSS. 207630.1-20260930212758-covered… Resistance can also occur without antigen loss through HER2 binding-site mutations such as: V597M P593R which preserve surface expression but reduce trastuzumab binding. So a biopsy saying: “HER2 PRESENT” does not necessarily mean: “T-DXd CAN STILL BIND EFFECTIVELY.” 💣 PAYLOAD resistance may be equally important A tumor can preserve the ADC target but become resistant to its warhead. Examples include: lysosomal dysfunction SLC46A3 loss caveolin-mediated trafficking changes STAT3 activation PLK1 activation ABCC1 drug efflux. 207630.1-20260930212758-covered… And perhaps most strikingly: TOP1 MUTATIONS were detected in: 12.9% of patients progressing after TOP1i ADCs versus 0.7% in ADC-naive breast cancer. 207630.1-20260930212758-covered… Patients harboring these mutations had dramatically shorter responses to subsequent TOP1i ADCs: 52 vs 455 DAYS. 207630.1-20260930212758-covered… That provides a mechanistic explanation for: ADC CROSS-RESISTANCE. 🔁 This makes ADC SEQUENCING a major clinical problem Suppose a patient progresses on: T-DXd HER2 → DXd Should we switch to: SG TROP2 → SN-38? The antibody target changes. But both payloads inhibit: TOP1. Therefore: TARGET SWITCH ≠ MECHANISM SWITCH. Real-world analyses suggest cross-resistance is particularly problematic when sequential ADCs share payload mechanisms. 207630.1-20260930212758-covered… One multicenter study cited in the review found approximately: different payload class → ORR 22.6% same payload class → ORR 5.3% although PFS remained similar and these data remain retrospective. 207630.1-20260930212758-covered… This suggests future ADC sequencing may require something analogous to antimicrobial resistance testing: WHAT TARGET REMAINS? WHAT PAYLOAD IS THE TUMOR STILL SENSITIVE TO? 🧬 A future ADC biopsy may therefore need MULTI-DIMENSIONAL profiling Not simply: HER2 = 1+ but perhaps: HER2 abundance + spatial heterogeneity TROP2 abundance binding-site mutation status TOP1 status ABCC1 expression lysosomal function SLC46A3 DNA repair state TME penetration immune context. The review specifically highlights: quantitative immunofluorescence spatial antigen mapping and AI-assisted digital pathology as emerging approaches beyond conventional categorical IHC. 207630.1-20260930212758-covered… 🛡️ ADCs may also function as IMMUNOTHERAPY TOP1 inhibitor payloads can trigger: IMMUNOGENIC CELL DEATH including: calreticulin exposure HMGB1 release ATP release leading to: dendritic-cell activation → antigen presentation → T-cell priming. 207630.1-20260930212758-covered… The antibody component can additionally promote: ADCC via NK cells and ADCP via macrophages. Figure 3 on page 6 nicely illustrates how bystander killing, extracellular payload release, ADCC, ADCP, immunogenic cell death, stromal barriers and abnormal vasculature all interact within the TME. 207630.1-20260930212758-covered… So ADCs are potentially: TARGETED DELIVERY CHEMOTHERAPY IMMUNE MODULATION. 🔥 ADC + ICI combinations are already testing this idea In first-line PD-L1-positive advanced TNBC: SG + pembrolizumab improved PFS over chemotherapy + pembrolizumab in ASCENT-04. And in BEGONIA: Dato-DXd + durvalumab produced approximately: 80% ORR regardless of PD-L1 expression. 207630.1-20260930212758-covered… But the story is not universally positive. T-DXd + nivolumab has so far produced response rates broadly comparable with historical T-DXd monotherapy. And DAISY biomarker analyses did not show a clear increase in granzyme-B⁺ CD8 T cells during T-DXd therapy. 207630.1-20260930212758-covered… So: ICD IN MICE ≠ GUARANTEED ICI SYNERGY IN HUMANS. That translational distinction is important. 🧬 Another rational combination: ADC + PARP inhibition TOP1 inhibitors trap: TOP1 cleavage complexes on DNA. PARP inhibition can further prevent repair of this damage. Thus: TOP1i ADC PARPi = DNA DAMAGE AMPLIFICATION. 207630.1-20260930212758-covered… The interesting pharmacological idea is that ADC delivery may create a larger: TUMOR : NORMAL PAYLOAD GRADIENT allowing sequential ADC/PARPi dosing that might be too toxic if both drugs were delivered systemically. 🚀 But the FUTURE of ADCs may look nothing like chemotherapy This is perhaps the most exciting part of the review. The next generation expands along: THREE AXES 1️⃣ NEW TARGETS Beyond HER2 and TROP2: HER3 Nectin-4 mesothelin FOLR1 B7-H3 B7-H4 Claudin 18.2 LIV1 ROR1/ROR2 tissue factor. And even: CANCER-ASSOCIATED FIBROBLASTS or ENDOTHELIAL CELLS can become ADC targets. 207630.1-20260930212758-covered… That represents another conceptual shift: THE ANTIBODY DOESN'T EVEN HAVE TO TARGET THE CANCER CELL. A stromal target can function as an anchor for local payload release. 2️⃣ NEW PAYLOADS Future ADC-like conjugates may carry: 🧬 siRNA ♻️ PROTACs 🧲 molecular glues 🛡️ STING agonists 🔥 TLR7/8 agonists ☢️ radionuclides 💡 photosensitizers ☠️ immunotoxins ✍️ α-amanitin. 207630.1-20260930212758-covered… Table 4 on page 10 shows just how far the field has moved beyond conventional cytotoxic payloads. 207630.1-20260930212758-covered… Perhaps eventually the term: ANTIBODY–DRUG CONJUGATE will become too narrow. These are increasingly: ANTIBODY-GUIDED MOLECULAR DELIVERY PLATFORMS. 3️⃣ SMARTER ANTIBODIES Next-generation engineering includes: biparatopic ADCs → two epitopes on one antigen bispecific ADCs → two different antigens dual-payload ADCs → two different warheads probody ADCs → masked until activated in the TME Fc engineering → tune immunity / half-life
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leoncologo's profile image
Luis A. Romero @leoncologo
Finally! A new generation Her2 ADC with a non topoisomerase inhibitor payload! Still too soon to talk about sequencing?
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The ASCO Post @ASCOPost
In a phase 3️⃣ trial, trastuzumab botidotin improved median PFS vs ado-trastuzumab emtansine in previously treated HER2+ advanced #BreastCancer: 11.1 vs 4.4 months. ➡️ The benefit was consistent across prespecified subgroups ▪️Xichun Hu, MD | @JCO_ASCO 🔗 https://t.co/G2DyUHoHf5
ASCOPost's tweet photo. In a phase 3️⃣ trial, trastuzumab botidotin improved median PFS vs ado-trastuzumab emtansine in previously treated HER2+ advanced #BreastCancer: 11.1 vs 4.4 months. ➡️ The benefit was consistent across prespecified subgroups ▪️Xichun Hu, MD | @JCO_ASCO 🔗 https://t.co/G2DyUHoHf5 https://t.co/ygxwVvqvrr
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leoncologo  retweeted
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Yakup Ergün Verified account @dr_yakupergun
Anthracyclines in Early Breast Cancer: The Long Goodbye 💥The era of anthracycline-based chemotherapy in early breast cancer is fading, with newer treatments offering safer and more effective options for many patients https://t.co/JYG0couV7m
dr_yakupergun's tweet photo. Anthracyclines in Early Breast Cancer: The Long Goodbye 💥The era of anthracycline-based chemotherapy in early breast cancer is fading, with newer treatments offering safer and more effective options for many patients https://t.co/JYG0couV7m https://t.co/73psoiZrP1
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W Radio México Verified account @WRADIOMexico
#AlAire @enfinw969 | Luis Alfonso Romero Robles, Oncologo Medico egresado del Hospital 20 de Noviembre, adscrito en el Hospital General de León y miembro de la Sociedad Mexicana de Oncología Cómo detectar el cáncer de piel a tiempo Con @LopezElizondo11 y @marycarmenlara_ 🎙️ @leoncologo •Por el 96.9 FM o el 900 AM📻 •Conéctate #EnVivo https://t.co/rackhIHSKE •O en nuestra app https://t.co/qBIQ75XEF7📲
WRADIOMexico's tweet photo. #AlAire @enfinw969 | Luis Alfonso Romero Robles, Oncologo Medico egresado del Hospital 20 de Noviembre, adscrito en el Hospital General de León y miembro de la Sociedad Mexicana de Oncología Cómo detectar el cáncer de piel a tiempo Con @LopezElizondo11 y @marycarmenlara_ 🎙️ @leoncologo •Por el 96.9 FM o el 900 AM📻 •Conéctate #EnVivo https://t.co/rackhIHSKE •O en nuestra app https://t.co/qBIQ75XEF7📲
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Paul Wischmeyer MD @Paul_Wischmeyer
Ten simple Rules for making good Oral presentation @ScholarshipfPhd
Paul_Wischmeyer's tweet photo. Ten simple Rules for making good Oral presentation @ScholarshipfPhd https://t.co/TzXw1yjaCx
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leoncologo  retweeted
kevinpunie's profile image
Kevin Punie @kevinpunie
#ESMOBreast24 @CarmenCriscit provides excellent guidance in decision making between #olaparib and #abemaciclib in patients with early-stage high-risk HR+/HER2- #breastcancer with overlapping indications @E_de_Azambuja @ErikaHamilton9 @myESMO ⁩ #ESMOAmbassadors #bcsm
kevinpunie's tweet photo. #ESMOBreast24 @CarmenCriscit provides excellent guidance in decision making between #olaparib and #abemaciclib in patients with early-stage high-risk HR+/HER2- #breastcancer with overlapping indications @E_de_Azambuja @ErikaHamilton9 @myESMO ⁩ #ESMOAmbassadors #bcsm https://t.co/mtc8I6CDSx
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leoncologo  retweeted
Annals_Oncology's profile image
Annals of Oncology @Annals_Oncology
Presented by @RebeccaDSing at #ESMOBreast24 w/ simultaneous publication in Annals of Oncology 1st results of Impassion132 showing no benefit of adding #atezoliyumab to 1st line CT in pts w/ advanced #TNBC relapsing &lt;12months. #AnnOnc #BreastCancer https://t.co/DXTDJ38uhx
Annals_Oncology's tweet photo. Presented by @RebeccaDSing at #ESMOBreast24 w/ simultaneous publication in Annals of Oncology 1st results of Impassion132 showing no benefit of adding #atezoliyumab to 1st line CT in pts w/ advanced #TNBC relapsing &lt;12months. #AnnOnc #BreastCancer https://t.co/DXTDJ38uhx https://t.co/7YJKEK5M70
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leoncologo  retweeted
PTarantinoMD's profile image
Paolo Tarantino Verified account @PTarantinoMD
Incredibly excited to see our article on optimizing the safety of ADCs making it to the cover of the August issue of @NatRevClinOncol! Also, glad to announce that the article will be open access for the next month! Read it here: https://t.co/QcpeKTosCq
PTarantinoMD's tweet photo. Incredibly excited to see our article on optimizing the safety of ADCs making it to the cover of the August issue of @NatRevClinOncol! Also, glad to announce that the article will be open access for the next month! Read it here: https://t.co/QcpeKTosCq https://t.co/FyepcOCt8J
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leoncologo's profile image
Luis A. Romero @leoncologo
· San Pedro Garza García
Neoadyuvancia en Melanoma. Sesión de residentes Monterrey 2023 con invitado de lujo el Dr. Michael Wong.
leoncologo's tweet photo. Neoadyuvancia en Melanoma. Sesión de residentes Monterrey 2023 con invitado de lujo el Dr. Michael Wong. https://t.co/7e9akuPjnY
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leoncologo's profile image
Luis A. Romero @leoncologo
Nuevos tratamientos, nuevas toxicidades. No es sólo identificar quien se beneficia, si no también quien tiene algún riesgo.
PTarantinoMD's profile image
Paolo Tarantino Verified account @PTarantinoMD
Wonderful study: 9/13 pts with ICI-related diabetes had germline mutations in NLRC5, with a significantly higher incidence than the general population. Toxicity biomarkers should be a priority of cancer research, particularly given the expanding use of IO in the curative setting.
PTarantinoMD's tweet photo. Wonderful study: 9/13 pts with ICI-related diabetes had germline mutations in NLRC5, with a significantly higher incidence than the general population. Toxicity biomarkers should be a priority of cancer research, particularly given the expanding use of IO in the curative setting. https://t.co/JfW9eu7Uof
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leoncologo  retweeted
IlanaSchlam's profile image
Ilana Schlam @IlanaSchlam
@TumorBoardTues @drsarahsam @MPishvaian @JohnEbbenMDPhD @darioT_ @curijoey @PTarantinoMD @ArielleMedford @prat_aleix @christeeny513 @TBlackburn25 @matteolambe @maur_jmp @oesterreichs @CCortiMD @ehgkulow @khewittmd @laura_huppert @amybeumer @JaniceTNBCmets @ASridharMD @masreya_dr @ramsedhom @RodriguezGIMD @DrAmyComander @antoinedardenn1 @AnnPartridgeMD @Dr_RShatsky @jhaveri_komal @DrGattiMays @nlinmd @prarthnavb @DrTimothyErick @SemberQuinne @LEForrest @DrSGraff @KoontzOncology @AdrianaKahnMD @quirogad @vandanaraman @RenataArakelian @DFCI_BreastOnc @ErikaHamilton9 @TuftsMedicalCtr @ThanksCancer @TariKingMD @DrJamesJakub @SheydaDoc @NicoleKuderer 5/17 #TumorBoardTuesday 👩🏻‍🏫Mini tweetorial 2👩🏻‍🏫 🌟CDK4/6 after CDK4/6 trials @StoverLab summarized #ASCO23 (see table👇) Continuation of CDK4/6i after progression &amp; switch to FULV with mixed results: ➕MAINTAIN: mostly ribo after palbo ➖PACE &amp; PALMIRA: mostly palbo after palbo
IlanaSchlam's tweet photo. @TumorBoardTues @drsarahsam @MPishvaian @JohnEbbenMDPhD @darioT_ @curijoey @PTarantinoMD @ArielleMedford @prat_aleix @christeeny513 @TBlackburn25 @matteolambe @maur_jmp @oesterreichs @CCortiMD @ehgkulow @khewittmd @laura_huppert @amybeumer @JaniceTNBCmets @ASridharMD @masreya_dr @ramsedhom @RodriguezGIMD @DrAmyComander @antoinedardenn1 @AnnPartridgeMD @Dr_RShatsky @jhaveri_komal @DrGattiMays @nlinmd @prarthnavb @DrTimothyErick @SemberQuinne @LEForrest @DrSGraff @KoontzOncology @AdrianaKahnMD @quirogad @vandanaraman @RenataArakelian @DFCI_BreastOnc @ErikaHamilton9 @TuftsMedicalCtr @ThanksCancer @TariKingMD @DrJamesJakub @SheydaDoc @NicoleKuderer 5/17 #TumorBoardTuesday 👩🏻‍🏫Mini tweetorial 2👩🏻‍🏫 🌟CDK4/6 after CDK4/6 trials @StoverLab summarized #ASCO23 (see table👇) Continuation of CDK4/6i after progression &amp; switch to FULV with mixed results: ➕MAINTAIN: mostly ribo after palbo ➖PACE &amp; PALMIRA: mostly palbo after palbo https://t.co/jXcTNbWJBW
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leoncologo  retweeted
E_de_Azambuja's profile image
Evandro de Azambuja, MD, PhD @E_de_Azambuja
I remember when the idea of a new journal was first discussed... and not #impact factor 7.3! 🙌 Congratulations @cczielinski for this important achievement and for @myESMO initiative! @OncoAlert @ElsevierConnect
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leoncologo's profile image
Luis A. Romero @leoncologo
¿Qué placer oculto existe en ver fotografías de médicos con los brazos cruzados?
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leoncologo's profile image
Luis A. Romero @leoncologo
· Chicago
All set for ASCO 2023 Plenary Session #ASCO2023 #oncology #cancer
leoncologo's tweet photo. All set for ASCO 2023 Plenary Session #ASCO2023 #oncology #cancer https://t.co/e4C07tbcZW
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leoncologo  retweeted
sciencelinkonco's profile image
ScienceLink Verified account @sciencelinkonco
#Podcast #PasedeVisita Dr. Luis Alfonso Romero (@leoncologo), Dr. Jorge Arturo Alatorre (@JorgeAlatorreA1), Dra. Hazael Rodríguez y Dr. Efraín Camarín. En colaboración con la Sociedad Mexicana de Oncología A.C. https://t.co/wUk3mWZ4jT
sciencelinkonco's tweet photo. #Podcast #PasedeVisita Dr. Luis Alfonso Romero (@leoncologo), Dr. Jorge Arturo Alatorre (@JorgeAlatorreA1), Dra. Hazael Rodríguez y Dr. Efraín Camarín. En colaboración con la Sociedad Mexicana de Oncología A.C. https://t.co/wUk3mWZ4jT https://t.co/2w63myjryp
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leoncologo  retweeted
raffcolo's profile image
Raffaele Colombo @raffcolo
Antibody drug conjugates: The dos and don'ts in clinical development https://t.co/Fyk9GO6qOQ A must read! Online in the summer, and finally published in the December issue! @TonyTolcher
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leoncologo  retweeted
sciencelinkonco's profile image
ScienceLink Verified account @sciencelinkonco
#Podcast #PasedeVisita Dr. Luis Alfonso Romero (@leoncologo), Dra. Claudia Arce, Dra. Adriana Duarte y Dr. Francisco Tapia En colaboración con la Sociedad Mexicana de Oncología (@SMEOMX) https://t.co/02rAv5iNXW
sciencelinkonco's tweet photo. #Podcast #PasedeVisita Dr. Luis Alfonso Romero (@leoncologo), Dra. Claudia Arce, Dra. Adriana Duarte y Dr. Francisco Tapia En colaboración con la Sociedad Mexicana de Oncología (@SMEOMX) https://t.co/02rAv5iNXW https://t.co/9avlzBmtZO
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leoncologo  retweeted
matteolambe's profile image
Matteo Lambertini, MD PhD @matteolambe
Updated results from #MONARCH3 at #ESMO22: addition of #abemaciclib to an aromatase inhibitor improves overall survival in endocrine sensitive advanced #bcsm (not significant at this interim analysis but to me clinically relevant: mOS=67 months, &gt;1y gain) @OncoAlert @myESMO
matteolambe's tweet photo. Updated results from #MONARCH3 at #ESMO22: addition of #abemaciclib to an aromatase inhibitor improves overall survival in endocrine sensitive advanced #bcsm (not significant at this interim analysis but to me clinically relevant: mOS=67 months, &gt;1y gain) @OncoAlert @myESMO https://t.co/Y29qTirNia
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leoncologo's profile image
Luis A. Romero @leoncologo
Ninguna mujer en el mundo debería morir por cáncer cervicouterino. El único cáncer prevenible hasta hoy, indignante que esto siga pasando. #cervicalcancer #vph #vphvaccine
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