China's Bispecific ADCs Take Center Stage at AACR 2024 Amid Fierce Innovation Race

Author

｜Wheat

On December 12, 2023, Biokin announced that it had licensed the global rights (excluding mainland China) of its first EGFR×HER3 bispecific antibody-drug conjugate (ADC), BL-B01D1, to Bristol-Myers Squibb (BMS).The total potential deal value could reach up to 8.4 billion US dollars, breaking the record for China's innovative drug overseas licensing.

Recently, the CDE website indicated that BL-B01D1 is proposed for inclusion in the breakthrough therapy designation for second-line and above treatment of recurrent or metastatic nasopharyngeal carcinoma patients, with the potential to become the first approved bispecific antibody-drug conjugate (ADC).

These developments have also sparked enthusiasm for the research and development of bispecific antibody-drug conjugates (ADCs).**Currently, there is no bispecific antibody A globally.DCApproved for marketing,**But its research and development is in full swing,Major biotech companies are entering the field。This article reviews the latest advancements in bispecific antibody-drug conjugates (ADCs) disclosed at this year's AACR (China section).

01

Innovent Bio:

IBI3001

IBI3001 was developed by Innovent Bio based on its

B7-H3/EGFR

IBI334 is a B7-H3/EGFR bispecific antibody ADC drug developed by Innovent Bio.

Site-specific conjugation

The method, which was selected as a breakthrough research for the 2024 AACR (

Late-Breaking Research

)(Figure 1)[1].

Figure 1. AACR Abstract of IBI3001

Previously, Innovent Bio

As demonstrated in the IBI334 study:

1. B7-H3 and EGFR are co-expressed in multiple solid tumors;

2. B7-H3-assisted EGFR signaling inhibition is significantly superior to the EGFR monoclonal antibody Zalutumumab and the c-met/EGFR bispecific antibody Amivantamab;

3. IBI334 demonstrated good safety in cynomolgus monkeys at a dose of 120 mg/kg/week.

Based on this optimized bispecific antibody,

Innovent Bio

Site-specific conjugation of IBI334 with Exatecan (drug-to-antibody ratio = 4) using the clinically validated SyntecanE platform generates the bispecific ADC drug IBI3001.

。

IBI3001 has enhanced multiple mechanisms of action: 1. EGFR signal blockade; 2. EGFR and B7-H3 mediated payload internalization and cytotoxicity; 3. Bystander killing effect of ADC.

IBI3001 demonstrated effective in vitro cytotoxicity in all B7-H3 low EGFR low, B7-H3 high EGFR low, B7-H3 low EGFR high, and B7-H3 high EGFR high cancer cells across multiple solid tumors, including lung cancer, colorectal cancer, pancreatic cancer, breast cancer, head and neck cancer, and gastric cancer.

In addition,

It also has a strong bystander effect, capable of killing EGFR+ B7-H3+ cancer cells and EGFR- B7-H3- cancer cells.

。

IBI3001 in

Potent tumor growth inhibition was observed in NCI-H508 (colorectal cancer), JIMT-1 (breast cancer), BxPC3 (pancreatic cancer), and NCI-1975 (lung cancer) xenograft models.

, in BALB/c mice

With good PK characteristics, the half-life is 282 hours.

, and was well tolerated in cynomolgus monkeys at doses up to 90 mg/kg/week.

In summary, IBI3001 is a novel bispecific ADC that demonstrates strong anti-tumor efficacy across multiple solid tumors, with excellent pharmacokinetics and safety.

At the same time,

On April 5, Innovent Bio registered on ClinicalTrials.gov

Registered on

A Phase 1/2 Multicenter Study of IBI3001

A multi-regional, open-label, first-in-human study for the treatment of patients with unresectable, locally advanced or metastatic solid tumors (Figure 2).

It includes a Phase 1 portion to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of IBI3001, and a Phase 2 portion to explore and confirm the efficacy, safety, and tolerability of IBI3001 at the RP2D.

Figure 2. Phase 1/2 Clinical Trial of IBI3001

02

Orange Sail Pharmaceuticals: VBC101-F11 and VBC103

Orange Sail Pharmaceuticals at this year's AACR conference

Two Targeted Bispecific AD

C

The preclinical study was selected for Late-Breaking Research,

Including VBC101-F11 and VBC103 (Figures 3 and 4) [2,3].

VBC101-F11（EGFR/cMet）****

VBC101-F11 is a targeted therapy developed by Orange Sail Pharmaceuticals.

EGFR/cMet Bispecific ADC

, with a DAR of 4, this innovative design differentiates VBC101-F11 from other EGFR/cMet-targeted drugs on the market or in clinical trials (such as ABBV399 or AZD9592), optimizing both efficacy and safety.

Figure 3. AACR Abstract of VBC101-F11

VBC101-F11 has a low-affinity EGFR arm and a high-affinity cMet arm.

. Compared with ABBV-399 (which only targets cMet),

Incorporating a low-affinity EGFR arm can enhance binding affinity and internalization.

, thereby generating better cytotoxicity

This meticulous EGFR arm design ensures the reduction of off-target toxicity associated with EGFR in normal tissues.

The biparatopic design of the cMet group exhibits synergistic effects in binding, internalization, and functional blockade, enhancing cytotoxicity compared to monospecific parental antibodies targeting a single epitope.

times, ensuring the maximum efficacy of VBC101-F11 in tumor cells.

VBC101-F11 Innovative Based on

Nanobody

The specifications make it stand out. In vivo imaging data in mouse models show that VBC101-F11 (90kD) achieved superior tumor penetration and accumulation from 1 hour to over 90 hours, surpassing both ABBV399 and the bispecific antibody AZD9592, both of which are 150kD.

VBC101-F11 Demonstrates Excellent Molecular Developability in Stress Tests, Particularly Showing Significant Stability of Both Antibody Components and the Entire ADC Molecule in Human and Non-Human Primate (NHP) Plasma, Making VBC101-F11 a Viable Candidate for Future Chemistry, Manufacturing, and Control (CMC) Development.

In in vivo CDX models using various lung cancer cell lines, compared with ABBV-399,

VBC101-F11 Demonstrates Significant Advantage in Tumor Growth Inhibition at a Single Dose of 3mg/kg (TGI 60% vs. 17%)

。

Further exploration of effective payloads, such as DNA replication inhibitors, has also yielded promising results. The VBC101-F11-new payload demonstrated efficacy comparable to the peer ADC AZD9592 in models with low EGFR and high cMet expression (100% TGI) and in models with moderate EGFR/cMet expression (~60% TGI).

In summary, VBC101-F11 features a unique design and exceptional properties, demonstrating remarkable potential in the field of anti-EGFR/cMet therapy. The encouraging efficacy observed in preclinical models supports the molecule's progression into clinical development, positioning it as a first-in-class bispecific ADC for cancer treatment.

VBC103（Trop2/Nectin4）****

VBC103 is a targeted therapy developed by Orange Sail Pharmaceuticals.

Trop2 and Nectin4 Bispecific ADC

, Trop2 and Nectin4 in

Urothelial Carcinoma (UC), Triple-Negative Breast Cancer

(TNBC) and other tumors (Figure 4).

Figure 4. AACR Abstract of VBC103

VBC103 provides tumor cells with a TOPOi payload that has a strong bystander effect, maximizing efficacy while minimizing safety concerns.

VBC103 has the following characteristics that distinguish it from other drugs targeting Trop2 or Nectin4, which are either in clinical development or already on the market.

a. Compared with Nectin4 monoclonal antibody or approved Nectin4 ADC

Padcev

In comparison,

VBC103 exhibits enhanced binding affinity, internalization, and cytotoxicity.

Moreover, the moderate affinity of VBC103 for Trop2 and Nectin4 helps reduce target-driven toxicity in normal tissues.

b. Compared with Enfortumab (MW 150kDa), the innovative format of VHH-Fc fusion protein (MW 90kDa)

Showing superior tumor penetration, accumulation (MFI ratio in tumors: 280 VS 174), and distribution (MFI ratio in the liver: 10 VS 18).

。

c. And

Padcev

Compared to the payloads used in, TOPOi payloads have a stronger bystander cell-killing effect.

d.VBC103's

Superior efficacy in vivo

, in the UC CDX model, TGI 95% [VBC103, 5 mpk] vs 77% [

Padcev

，8 mpk] vs 70% [

Padcev

+SG, 4+4 mpk] (Q3Wx 3; ADC molecular equivalent) on Day 42 post-injection. In the TNBC CDX model, VBC103 was administered as a single-dose treatment on Day 21 post-injection, showing comparable results to

Padcev

(Maximum Tolerated Dose) showed consistently superior efficacy compared to SG.

e.VBC103 is available.

Wider therapeutic window

(TW). Preliminary toxicity studies in cynomolgus monkeys showed that repeated doses (18 and 36 mpk) of VBC103 were well tolerated, with VBC103 being molecularly equivalent to 30 and 60 mpk of IgG1 ADC. These findings can determine TW as >10 (HNSTD/MED).

f. Based on plasma stability and other stress test data, VBC103 also demonstrated excellent developability, indicating that it is a strong candidate for future CMC development.

In summary, VBC103, with its unique bispecific design and differentiated features in affinity, valency, and linker payload, demonstrates potential as a first-in-class ADC candidate. Discovery research has revealed favorable efficacy and toxicity profiles, supporting the advancement of VBC103 into clinical trials.

03

Alphamab Oncology: JSKN003

JSKN003 is a product developed by Alphamab Oncology.

Bispecific HER2-targeted ADC

, conjugated through a tetrapeptide linker with dibenzocyclooctyne on the glycan of a humanized bispecific antibody and a topoisomerase I inhibitor (TOP1i).

At this year's AACR conference, Claire et al. reported the early clinical efficacy and safety data of JSKN003. As of December 15, 2023, a total of 32 patients (15 with breast cancer, 5 with ovarian cancer, 3 with bladder cancer, 2 with esophageal cancer, 2 with non-small cell lung cancer, 1 with gastric cancer, 1 with head and neck cancer, and 3 with other cancers) were enrolled and received JSKN003 at seven dose levels (1.0, 2.1, 4.2, 5.2, 6.3, 7.3, and 8.4 mg/kg, Q3W) [4].

Figure 5. AACR Abstract of JSKN003

The median treatment duration was 15.8 weeks (range, 6-54 weeks), with 19 patients (59.4%) still on treatment. Treatment-related adverse events (TRAEs) occurred in 27 patients (84.4%), including 2 cases (6.3%) of grade 3 TRAEs (anemia and fatigue) at doses of 4.2 mg/kg and 7.3 mg/kg, respectively. The most common TRAEs were diarrhea (62.5%) and nausea (50.0%), all of which were grade 1-2. Only one patient experienced interstitial lung disease (7.3 mg/kg, grade 2). To date, no dose-limiting toxicity (DLT) events have been observed, and no TRAEs have led to death or treatment discontinuation.

In

8.4 mg/kg

Time

MTD Not Yet Reached

。

After a single dose, the exposure (Cmax and AUC) of JSKN003 and the released TOP1i increased proportionally in the dose range of 4.2mg/kg to 8.4mg/kg. For doses of 6.3mg/kg and higher, the T1/2 of JSKN003 was approximately 5-6 days and increased with the dose.

。

All patients underwent at least one tumor assessment after baseline. 16 cases achieved a partial response according to RECIST 1.1 as evaluated by the investigators.

The objective response rate (ORR) and disease control rate (DCR) were 50.0% and 90.6%, respectively.

。

04

Profound Bio: PRO1286

PRO1286 is developed by Provention Bio

Conjugated from a monovalent bispecific human IgG1 with affinity for EGFR and cMET, and sesutecan, a proprietary linker drug based on a topoisomerase 1 inhibitor, using its proprietary technology platform.

EGFR and cMET Bispecific ADC

(Figure 6) [

5]

。

Figure 6. AACR Abstract of PRO1286

At a DAR of 8, PRO1286 exhibits high hydrophilicity and excellent stability and developability in vitro.

PRO1286 selectively and specifically binds to each target, exhibiting low nanomolar EC in CHO-K1 cells overexpressing each target.

50

。

PRO1286 demonstrated significant dose-dependent anti-tumor activity in a mouse xenograft model, even

Sustained tumor growth inhibition or complete remission was observed in several xenograft models after treatment with a single dose (2mg/kg) of PRO1286.

。

In the exploratory toxicity study of cynomolgus monkeys,

PRO1286 was well tolerated at 30 mg/kg

, The main toxicity is payload-driven and resides in the bone marrow.

PRO1286 Exhibits

Stable PK Characteristics

, showing PK characteristics similar to those of dual antibodies in rats and good PK characteristics in monkeys.

05

DAC Biotech: DXC024 and DXC025

DXC024 was developed by DAC Biotech with the selected

Trop2/EGFR Bispecific Antibody Conjugated with Tubulysin B Analogues via Multiple Peptide-Based Linkers to Generate Bispecific ADC

, which exhibited strong cytotoxic activity in A431, MDA-MB-468, Calu3, and MCF-7 cells (Figure 7) [6].

In vivo, DXC024 demonstrated excellent and durable anti-tumor responses at a single low dose of 4.6 mg/kg in the Calu3 (TROP2 high, EGFR moderate expression) xenograft model, showing stronger anti-tumor efficacy compared to the same payload conjugated with monoclonal TROP2 or EGFR ADC.

Figure 7. AACR Abstract of DXC024

DAC Biotech designed and generated using the knob-into-hole technology

Targeting MUC1 and EGFR

The bispecific Fab/scFv antibody, followed by conjugation of the selected BsAb with Tubulysin B analog payloads and functional peptide-based spacers/linkers to generate the bispecific ADC drug DXC025.

DXC025 demonstrates highly effective cytotoxicity in vitro against epidermal carcinoma, lung adenocarcinoma, and pancreatic cancer cell lines.

In the cell-derived xenograft (CDX) model in vivo, DXC025 demonstrated better tumor growth inhibition efficacy in treating gastrointestinal tumors compared to the parental Muc1- or EGFR-ADC (Figure 8) [7].

Figure 8. AACR Abstract of DXC025

06

Biocytogen: BCG016, BCG017, and BCG019

At this year's AACR conference, Biocytogen presented advancements in multiple bispecific ADCs, including BCG016, BCG017, and BCG019.

First, Biocytogen constructed the selected antibody into a 5T4 × MUC1 bispecific antibody. Subsequently, the 5T4-MUC1 bsAb was conjugated with MMAE to generate the 5T4 x MUC1 bispecific ADC drug BCG016.

Cytotoxicity assays showed that, compared with the benchmark ADC, BCG016 enhanced tumor cell killing in vitro. In vivo efficacy studies demonstrated that BCG016 exhibited superior antitumor efficacy in patient-derived NSCLC xenografts compared with the benchmark ADC and the combination therapy of the parent ADC (Figure 9) [8].

Figure 9. AACR Abstract of BCG016

Biocytogen has developed a fully human anti-human PTK7 EGFR bsAb by using its proprietary universal light chain RenLite® mouse platform and knob-into-hole technology.

Next, conjugate this bsAb with MMAE to generate the PTK7 x EGFR bispecific antibody ADC drug BCG017, with a drug-to-antibody ratio of approximately 4.

Compared with the benchmark and its PTK7 parental ADC, BCG017 demonstrated superior anti-tumor activity in non-small cell lung cancer (NSCLC) xenograft models, and also showed enhanced anti-tumor activity in patient-derived breast cancer and pancreatic ductal adenocarcinoma xenograft models. These results suggest that BCG017 has the potential to become a novel therapeutic option for tumors co-expressing PTK7 and EGFR (Figure 10) [9].

Figure 10. AACR Abstract of BCG017

Biocytogen

A fully human bispecific antibody targeting EGFR and HER3 was generated using RenLite® mice.

A bispecific ADC candidate drug, BCG019, targeting EGFR and HER3, is generated by conjugating the payload through a highly hydrophilic protease-cleavable linker.

Compared with the benchmark ADC, BCG019 demonstrated superior anti-tumor activity in cell-derived NSCLC and gastric cancer xenografts as well as patient-derived gastric and colorectal xenograft models (Figure 11) [10].

Figure 11. AACR Abstract of BCG019

In addition, Biocytogen has also developed HER3/Met bispecific ADC drug BCG022 and PTK7/Trop-2 bispecific ADC drug BCG033, etc.

07

Promab Bio: PM1300

PM1300 is

EGFR x HER3 Bispecific ADC Generated by Primoris Bio through Introducing Unique Mutations into the CH1-CL Domains of Each Binding Arm

, TOP1i payload is conjugated to the IgG-like bispecific antibody through a cleavable linker at the endogenous cysteine residues of DAR 8 sites.

PM1300 significantly increases the internalization and anti-proliferative activity in EGFR/HER3 double-positive cells, with limited activity in single-positive cells. PM1300 uses an optimized linker to achieve better payload release and serum stability.

PM1300 demonstrated potent antitumor efficacy in various CDX models representing different EGFR and HER3 expression levels and mutations. Moreover, PM1300 exhibited favorable safety in non-human primates, consistent with optimal affinity for EGFR and HER3. These results indicate that PM1300 has a favorable efficacy/safety therapeutic window in preclinical models, supporting further clinical development (Figure 12) [11].

Figure 12. AACR Abstract of PM1300

08

Stellar Origins: NXV01c

NXV01c was developed by Neox Biotech.

The First

Targeted

EGFR×cMET Bispecific Nanobody Conjugate.

Xingkangyuan screened lead nanobodies against EGFR and cMET from immune libraries using phage display, then efficiently humanized and optimized them using neoX's computational platform. Next, a bispecific nanobody with Fc (NXV01) was constructed through "knob-into-hole" heterodimerization, followed by uniform conjugation with MMAE via a lysosome-cleavable valine-citrulline dipeptide linker (Figure 13) [12].

Figure 13. AACR Abstract of NXV01c

NXV01c exhibits high uniformity: its average DAR is 3.87, and >95% of NXV01c has a DAR of 4.

In vitro, NXV01c rapidly internalized into H1975 cells co-expressing EGFR and cMET. NXV01c inhibited the growth of H1975 (lung) and SNU5 (gastric) cancer cells while sparing normal keratinocytes, and also suppressed the proliferation of other cell lines derived from lung, gastric, esophageal, and liver cancers, with the level of inhibition positively correlated with the expression density of the two targets.

In the H1975 cell line-derived xenograft model, NXV01C demonstrated effective and dose-dependent antitumor activity.

Treatment once a week at doses of 3 mg/kg and 10 mg/kg for 2 weeks led to tumor shrinkage and complete regression, respectively.

。

In patient-derived xenograft models of non-small cell lung cancer and esophageal cancer, NXV01C induced tumor regression and elimination without significant toxic effects. The EGFR×cMET bispecific nanobody drug conjugate NXV01C demonstrated favorable drug-like properties and exhibited excellent anti-tumor efficacy both in vitro and in vivo. The results indicate that NXV01C can effectively treat EGFR/cMET-harboring tumors commonly found in various malignant cancers.

09

Sida Pharmaceuticals

DM002

DM002 is a novel bispecific ADC drug targeting HER3 and MUC1, developed by Sidao Pharmaceuticals using fully humanized antibodies obtained from the RenLite platform licensed from Biocytogen.

vcMMAE or conjugated with a novel DNA topoisomerase I inhibitor linker/payload conjugate (BLD1102) for preparation

And Get

。

Both dual-antibody ADCs effectively inhibited the growth of HER3+MUC1+PDX tumors. DM002-vcMMAE also demonstrated higher in vivo efficacy compared to its parent monoclonal antibody ADCs, consistent with their in vitro internalization activity (Figure 14) [13].

DM002-BLD1102 also demonstrated potent antitumor activity in DM002-vcMMAE-resistant PDX models, indicating that this novel DNA topoisomerase I inhibitor linker/payload is superior to the classic vcMMAE linker/payload. In summary, the HER3 × MUC1 bsAb is a promising therapeutic agent for HER3 and MUC1-positive tumors.

Figure 14. AACR Abstract of DM002

Written at Last

In addition to the partial bispecific ADCs announced at the 2024 AACR,

Clinically

Also

There are many bispecific ADCs under research, such as ZW-49, MEDI4276, JSKN003, and AZD9592, etc. (Figure 15).

Figure 15. Partially clinically researched bispecific ADCs

Figure 16. In September 2023, Dr. Cexiong Fu discussed bispecific ADC at the BiG Forum.

The ADC market size exceeded 10 billion US dollars for the first time in 2023.

，

The market size is expanding year by year.

However, ADC drugs tend to induce resistance during the treatment progression.

To overcome ADC resistance and from the perspective of BD cooperation, many biotechs have started developing bispecific ADCs.

Dual-Targeting ADCs Although

Expected to improve existing clinical challenges associated with ADCs, particularly issues related to poor internalization, off-target toxicity, and drug resistance.

But the challenges are even greater. It is necessary to rationally view innovation and risks. Whether it can cross the chasm remains to be seen in the future!

Main References

1.Abstract LB055: IBI3001: A potentially first-in-class site-specifically conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors

2.Abstract LB043: VBC101-F11: An innovative EGFR/cMet bispecific antibody drug conjugate (ADC) targeting key oncogenic drivers in solid tumors

3.Abstract LB448: VBC103: An innovative Trop2/Nectin4 targeted bispecific antibody drug conjugate (ADC) in bladder urothelial carcinoma (UC), triple-negative breast cancer (TNBC) and beyond

4.Abstract CT179: Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study

5.Abstract 6580: A Novel EGFR x cMET bispecific ADC PRO1286 demonstrated broad antitumor activity and promising tolerability in preclinical models

6.Abstract 1882: DXC024, a novel anti-TROP2/EGFR bispecific antibody and tubulysin conjugate, for targeted treatment of highly TROP2- or EGFR-expressing tumors

7.Abstract 3147: DXC025, a novel anti-MUC1/EGFR bispecific antibody-tubulysin conjugate with a function linker, exhibits potent anti-tumor efficacy

8.Abstract 2620: BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity

9.Abstract 2618: BCG017, a bispecific ADC targeting PTK7 and EGFR exhibits anti-tumor efficacy in PDX models

10.Abstract 2619: A novel EGFR × HER3-targeting bispecific antibody drug-conjugate, BCG019, demonstrates robust anti-tumor efficacy in preclinical evaluation

11.Abstract 5083: Discovery of an asymmetric IgG-like bispecific ADC targeting EGFR/HER3

12.Abstract 1871: Discovery and characterization of NXV01c, an EGFR × cMET bispecific nanobody drug conjugate with potent anti-tumor activity

13.Abstract 2621: Preclinical Efficacy of DM002, a bispecific HER3 × MUC1 antibody-drug conjugate with a novel DNA topoisomerase I inhibitor, in solid tumor models

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