Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

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Novel Fc-Engineered Anti-B Cell Maturation Antigen-Monomethyl Auristatin F Antibody-Drug Conjugate (GSK2857916) Induces Potent and Selective Anti-Multiple Myeloma Activity Via Enhanced Effector Function and Direct Tumor Cell Killing

Blood ◽

10.1182/blood.v122.21.877.877 ◽

2013 ◽

Vol 122 (21) ◽

pp. 877-877

Author(s):

Yu-Tzu Tai ◽

Chirag Acharya ◽

Mike Y Zhong ◽

Michele Cea ◽

Antonia Cagnetta ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Cell Maturation ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

B Cell Maturation ◽

Equity Ownership ◽

B Cell Maturation Antigen ◽

Antibody Drug

Abstract B cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). We here investigated the anti-MM activity of J6M0-mcMMAF (GSK2857916), a humanized and afucosylated anti-BCMA antibody-drug conjugate (ADC) via uncleavable linker. This novel antagonist anti-BCMA antibody shows binding against all CD138-expressing MM cell lines (n=13) and patient MM cells (n=18), confirming universal BCMA expression on the surface of myeloma cells. Real-time qRT-PCR also showed significantly upregulated BCMA mRNA in CD138+ cells purified from MM patients vs. normal donors (p < 0.03). In contrast, BCMA is undetectable in CD138-negative cells from MM patients (n=3). J6M0-mcMMAF strongly blocks cell growth and induces caspase 3-dependent apoptosis in both drug-sensitive and -resistant MM cell lines and patient CD138+ MM cells, alone and in co-culture with BMSCs. In contrast, an isotype control antibody-drug conjugate (iso-mcMMAF) had no effect on viability of ANBL6 MM cells, alone or cocultured with BMSC. J6M0-mcMMAF specifically induces cell death in CD138-positive patient MM cells but not CD138-negative cells, demonstrating the minimal bystander killing against surrounding BCMA-negative cells. J6M0-mcMMAF completely blocks colony formation of MM cell lines (n=6) via induction of G2/M arrest, followed by apoptosis. This ADC does not affect viability of BCMA-negative NK, PBMC, and BMSCs, cultured alone or together, confirming its specific targeting of BCMA-positive MM cells. J6M0-mcMMAF, which has enhanced Fc-receptor binding due to afucosylation, significantly improved autologous antibody-dependent cellular cytotoxicity (ADCC) potency and maximum MM cell lysis against MM patient cells (n=5), when compared to J6M0 with normal Fc. Such augmented ADCC and maximum patient MM cell lysis by J6M0-mcMMAFis more pronounced in the autologous setting vs. the allogenic setting where MM cells and healthy donor effectors were used. Pretreatment of PBMC effector cells with lenalidomide further increased J6M0-mcMMAF-induced ADCC against MM cells in the presence or absence of BMSC. The in vivo efficacy of J6M0-mcMMAF was evaluated in murine subcutaneous xenograft models using NCI-H929 and OPM2 cells, as well as in NK-deficient SCID-beige mice with diffuse human MM bone lesions using MM1Sluc cells. Administration of J6M0-mcMMAF at 4 mg/kg (q3d x 4, ip) completely eliminated NCI-H929 and OPM2 xenograft tumors in all mice which remained tumor-free until the termination of studies at 60 and 100 days, respectively. In the MM1Sluc bone marrow dissemination model, J6M0-mcMMAF eradicates detectable tumors after 2 doses at 0.4 mg/kg (q3d x 9, ip), which resulted in extended survival (p<0.0001) and no weight loss of mice following 120 days. J6M0 treatment, although less effective than J6M0-mcMMAF, also had significantly prolonged survival (p<0.03) and diminished tumor burden when compared with control vehicle and isotype-treated groups, indicating a potential role of macrophage-mediated phagocytosis. Indeed, J6M0-mcMMAF recruits macrophage and mediates phagocytosis of target MM cells. Taken together, our studies show that J6M0-mcMMAF potently and selectively induce direct and indirect killing of MM tumor cells both in vitro and in vivo, providing a very promising next-generation immunotherapeutic in this cancer. Disclosures: Tai: Onyx: Consultancy. Mayes:GlaxoSmithKline: Employment. Craigen:GlaxoSmithKline: Employment. Gliddon:GlaxoSmithKline: Employment. Smothers:GlaxoSmithKline: Employment. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

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SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/neu expression.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14009 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14009-e14009

Author(s):

Gulden Menderes ◽

Elena Bonazzoli ◽

Stefania Bellone ◽

Jonathan Black ◽

Gary Altwerger ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Gynecological Cancer ◽

In Vivo Studies ◽

Her2 Overexpression ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Bystander Killing ◽

Antibody Drug

e14009 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. HER2 overexpression/amplification in EOC show considerable variation ranging from 8% to 66%. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to compare the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1) in EOC. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of effector cells [i.e., peripheral blood lymphocytes (PBL)] against EOC cell lines with high, moderate and low HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1. Specifically, in HER2/neu 1+ cell lines the mean IC50’s were 0.072 µg/mL and 3.035 µg/mL for SYD985 vs T-DM1 (p < 0.0001), in HER2/neu 2+ cell lines 0.054 µg/mL and 1.168 µg/mL, (p < 0.0001) and in HER2/neu 3+ cell lines 0.024 µg/mL and 0.088 µg/mL, respectively, (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in EOC and effective against HER2/neu 3+ xenografts. Additional (HER2/neu 2+ & 1+) EOC xenograft studies are ongoing. Conclusions: SYD985 is a novel ADC with remarkable in vitro activity against EOC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it may be active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in EOC patients harboring chemo-resistant disease are needed.

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Preclinical Development of an Anti-CD38 Antibody-Drug Conjugate for Treatment of Hematological Malignancies

Blood ◽

10.1182/blood-2019-132062 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5621-5621 ◽

Cited By ~ 1

Author(s):

Lingna Li ◽

Wenyong Tong ◽

Megan Lau ◽

Katherine Fells ◽

Tong Zhu ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Cell Binding ◽

Antibody Drug Conjugate ◽

Employment Equity ◽

Cd38 Expression ◽

Equity Ownership ◽

Anti Tumor Activity ◽

Antibody Drug

CD38 is a validated target for the treatment of multiple myeloma (MM). Daratumumab (Darzalex®), an anti-CD38 monoclonal antibody (mAb), has shown great clinical efficacy and has been approved for multiple myeloma treatment. However, both primary refractoriness and development of resistance to daratumumab therapy have been reported. Based on the therapeutic benefits of this CD38 antibody, we developed a CD38-targeting antibody-drug conjugate (ADC), employing a fully human anti-CD38 antibody STI-6129, identified from Sorrento's G-MAB® antibody library, and proprietary linker-toxin technology. The toxin payload is duostatin 5.2 (Duo.5.2), a microtubule inhibitor, conjugated to STI-6129 via a non-polyethylene glycol linker resulting in our lead ADC CD38-077. Cell binding studies showed that it specifically binds to CD38-positive tumor cells but not CD38-negative cell lines. The cell binding was proportional to the CD38 expression level on the cell surface. The ADC was internalized into CD38-positive cells at a rate comparable to that of the unconjugated antibody, indicating that conjugation did not change the binding characteristics of STI-6129 to its antigen. In cytotoxicity studies, CD38-077 exhibited a CD38-dependent cytotoxic activity against a panel of CD38-expressing tumor cell lines and was more potent in cells with high CD38 expression. The cytotoxic effect of CD38-077 was also examined against human PBMC cells, as it has been reported that certain types of the immune cells express CD38. The result indicated that normal PBMC cells were generally insensitive to the ADC up to 1 µM following 120 hr exposure. We investigated the anti-tumor activity of CD38-077 in xenograft animal models of Burkitt's lymphoma and two different multiple myeloma (MM) cell lines. The studies evaluated different dose levels and dosing regimens, including single dose and multiple doses at various intervals. The data showed that the ADC has a broad, potent and CD38-dependent in vivo efficacy in all three xenograft tumor models examined. In a pharmacokinetic study in naïve mice, CD38-077 was found to be stable, with T1/2 of about 7-11 days, comparable to that of the unconjugated STI-6129 antibody. In summary, CD38-077 exhibits strong anti-tumor activity in vitro and in vivo. The ADC showed specific activity towards CD38-expressing tumors but was less active against CD38-expressing normal PBMC cells, which express relatively low levels of CD38 level and where internalization was not detectable. These results warrant further development exploration of CD38-077. Disclosures Li: Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Fells:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Takeshita:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.

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Preclinical Development of a Bcma Targeting Antibody-Drug Conjugate with Novel Payload for Multiple Myeloma Therapy

Blood ◽

10.1182/blood-2019-132080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5623-5623

Author(s):

Andrew Hau ◽

Tong Zhu ◽

Rengang Wang ◽

Megan Lau ◽

Lingna Li ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Antibody Drug Conjugate ◽

Preclinical Development ◽

Employment Equity ◽

Drug Conjugate ◽

Equity Ownership ◽

Anti Tumor Activity ◽

Antibody Drug

BCMA (B-cell maturation antigen) is an integral membrane protein that belongs to the TNF receptor family with expression restricted to B cell lineage cells. The RNA is near universally detected in multiple myeloma (MM) cells and the protein is expressed on the surface of malignant plasma cells from patients with MM. In contrast, BCMA expression in normal tissues is very limited, making BCMA a promising target for antibody-drug conjugate (ADC) therapy. We have developed a BCMA-targeting ADC, employing a fully human anti-BCMA monoclonal antibody (mAb) identified from Sorrento's G-MAB antibody library, which was conjugated using proprietary Concortis linker-Duo 5.2 toxin technology resulting in BCMA-077 ADC. The mAb has a unique binding profile for BCMA and demonstrated strong preferential binding for BCMA-overexpressing cells but showed much less binding to lower BCMA-expressing cells. This property allows for more selective binding of the ADC on high BCMA-expressing cells, which are usually tumor cells while sparing low BCMA-expressing normal cells. In addition, we modified the Duo 5.2 payload decreasing the potency of the unconjugated toxin while retaining activity when conjugated to the mAb. The resulting ADC, BCMA-024, was compared to BCMA-077 using in vitro assays, including binding, internalization and cytotoxicity against tumor cell lines. The two ADCs exhibited strong activity and no difference in cytotoxic potency evident. The toxicity of the payload derivative was evaluated in a rodent model and it was found to be well tolerated not showing toxicity at a dose 10 times higher than the lethal dose of the parental toxin. Both ADCs carrying either the parental Duo 5.2 toxin or the derivative toxin payload were evaluated in vivo for anti-tumor activity in three different multiple myeloma xenograft models using different dose regimens. The data showed that both ADCs demonstrated potent BCMA-dependent in vivo anti-tumor activity in all xenograft BCMA-positive tumor models. The PK of the parental anti-BCMA mAb was investigated in non-human primates (NHP) and the parameters indicated a T1/2 of about 10 days. The GLP toxicity studies are ongoing. Our BCMA-ADCs have shown favorable anti-tumor activities combined with good safety profiles resulting in an expanded therapeutic window. The data make BCMA-077 and BCMA-024 promising candidates for continued preclinical development. Based on the totality of our preclinical data, we anticipate selecting a BCMA ADC clinical candidate for the treatment of multiple myeloma. Disclosures Hau: Concortis Biotherapeutics: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Wang:Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Li:Concortis Biotherapeutics: Employment, Equity Ownership. Li:Levena Biopharma: Employment, Equity Ownership. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.

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THE ANTI-CD25 ANTIBODY-DRUG CONJUGATE CAMIDANLUMAB TESIRINE (ADCT-301) PRESENTS A STRONG PRECLINICAL ACTIVITY BOTH AS SINGLE AGENT AND IN COMBINATION IN LYMPHOMA CELL LINES

Hematological Oncology ◽

10.1002/hon.134_2630 ◽

2019 ◽

Vol 37 ◽

pp. 323-324 ◽

Cited By ~ 1

Author(s):

F. Spriano ◽

C. Tarantelli ◽

G. Golino ◽

E. Gaudio ◽

L. Scalise ◽

...

Keyword(s):

Cell Lines ◽

Single Agent ◽

Lymphoma Cell ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Antibody Drug

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Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis

Cancers ◽

10.3390/cancers11081138 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1138 ◽

Cited By ~ 1

Author(s):

Hayashi ◽

Madokoro ◽

Yamada ◽

Nishida ◽

Morimoto ◽

...

Keyword(s):

Monoclonal Antibody ◽

Tumor Growth ◽

Cell Lines ◽

Mrna Synthesis ◽

Antibody Drug Conjugate ◽

Pol Ii ◽

Drug Conjugate ◽

Antibody Drug

Here, we report a novel antibody drug conjugate (ADC) with the humanized anti-CD26 monoclonal antibody YS110 and triptolide (TR-1). YS110 has an inhibitory activity against the CD26-positive tumor growth via the immunological and direct pathway, such as intra-nuclear transportation of CD26 and YS110, and suppressed transcription of RNA polymerase II (Pol II) subunit POLR2A. The ADC conjugated with YS110 and an antitumor compound triptolide (TR-1), which is an inhibitor for TFIIH, one of the general transcription factors for Pol II was developed. YS110 and triptolide were crosslinked by the heterobifunctional linker succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and designated Y-TR1. Antitumor efficacy of Y-TR1 against malignant mesothelioma and leukemia cell lines were assessed by the in vitro cell viability assay and in vivo assay using xenografted mouse models. Y-TR1 showed significant cytotoxicity against CD26-positive cell lines but not CD26-negative counterparts in a dose-dependent manner via suppression of mRNA synthesis by impairment of the Pol II activity. The tumors in xenografted mice administered Y-TR1 was smaller than that of the unconjugated YS110 treated mice without severe toxicity. In conclusion, the novel compound Y-TR1 showed antitumor properties against CD26-positive cancer cell lines both in vitro and in vivo without toxicity. The Y-TR1 is a unique antitumor ADC and functions against Pol II.

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Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker

Scientific Reports ◽

10.1038/s41598-021-99852-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marta Poblocka ◽

Akang Leonard Bassey ◽

Victoria M. Smith ◽

Marta Falcicchio ◽

Ana Sousa Manso ◽

...

Keyword(s):

Antibody Drug Conjugate ◽

In Vivo Models ◽

P53 Expression ◽

Drug Conjugate ◽

New Class ◽

Age Related ◽

Novel Approach ◽

Wide Range ◽

Antibody Drug

AbstractA wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.

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Combination of Camidanlumab Tesirine, a CD25-Targeted ADC, with Gemcitabine Elicits Synergistic Anti-Tumor Activity in Preclinical Tumor Models

Blood ◽

10.1182/blood-2020-137004 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Asma Jabeen ◽

Shiran Huang ◽

John A. Hartley ◽

Patrick H Van Berkel ◽

Francesca Zammarchi

Keyword(s):

Solid Tumor ◽

Synergistic Activity ◽

Publicly Traded ◽

Tumor Models ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Anti Tumor Activity ◽

Antibody Drug

Camidanlumab tesirine (ADCT-301) is an antibody-drug conjugate (ADC) comprised of HuMax®-TAC, a monoclonal antibody directed against human CD25, conjugated to the pyrrolobenzodiazepine dimer payload tesirine[1]. Currently, camidanlumab tesirine is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL) (NCT04052997) and in a Phase 1b clinical trial in patients with advanced solid tumors (NCT03621982). In pre-clinical studies, camidanlumab tesirine demonstrated strong and durable single agent activity in CD25-expressing lymphoma xenograft models[1] and in vitro it synergised with selected targeted agents[2]. Moreover, CD25-ADC, a mouse CD25 cross-reactive surrogate of camidanlumab tesirine, induced potent anti-tumor immunity against established syngeneic solid tumor models by depleting CD25-positive tumor-infiltrating T regulatory cells (Tregs) and it showed synergistic activity when combined with PD-1 blockade[3]. Here, we investigated the in vitro and in vivo anti-tumor activity of camidanlumab tesirine combined with gemcitabine, a common standard-of-care chemotherapeutic agent used both in a hematological and solid tumor clinical setting. In vitro, the combination of camidanlumab tesirine and gemcitabine was evaluated in three human-derived cancer cell lines (two HL and one anaplastic large cell lymphoma, ALCL) and resulted in synergistic activity as determined by the Chou-Talalay method. In vivo, camidanlumab tesirine was tested either alone (0.05 or 0.1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4) in the CD25-expressing ALCL Karpas299 xenograft model. At both ADC dose levels, combination with gemcitabine resulted in synergistic anti-tumor activity (coefficient of drug interaction (CDI) 0.51 and 0.17, respectively), better response rates and increased survival compared to monotherapy with camidanlumab tesirine. In order to extend the investigation to solid tumor models, CD25-ADC was tested in the CT26 syngeneic model, a colorectal cancer model with CD25-expressing tumor-infiltrating Tregs. CD25-ADC was administered either alone (0.1, 0.5 or 1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4). At the 0.1 mg/kg dose of CD25-ADC, combination with gemcitabine resulted in synergistic anti-tumor activity (CDI 0.68). Moreover, at 0.5 and 1 mg/kg, the combination of CD25-ADC and gemcitabine resulted in more durable anti-tumor activity and better response rates compared to both monotherapy treatments. In conclusion, the combination of camidanlumab tesirine and gemcitabine was synergistic both in vitro and in vivo in lymphoma preclinical models. Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic. 1.Flynn, M.J., et al., ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Mol Cancer Ther, 2016. 15(11): p. 2709-2721. 2.Spriano, F., et al., The anti-CD25 antibody-drug conjugate camidanlumab tesirine (ADCT-301) presents a strong preclinical activity both as single agent and in combination in lymphoma cell lines. Hematological Oncology, 2019. 37(S2): p. 323-324. 3.Zammarchi, F., et al., A CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer, 2020. In press. Disclosures Jabeen: ADC Therapeutics: Current Employment. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Van Berkel:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zammarchi:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company.

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Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats

Journal of Clinical Medicine ◽

10.3390/jcm10061323 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1323

Author(s):

Victor Yip ◽

M. Violet Lee ◽

Ola M. Saad ◽

Shuguang Ma ◽

S. Cyrus Khojasteh ◽

...

Keyword(s):

B Cell Lymphoma ◽

The United States ◽

Clinical Development ◽

Sprague Dawley ◽

Antibody Drug Conjugate ◽

Post Dose ◽

Drug Conjugate ◽

Sprague Dawley Rats ◽

A Minor ◽

Antibody Drug

Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

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