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Nonclinical safety evaluation of immunoconjuates

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1 Nonclinical safety evaluation of immunoconjuates
Antibody-Drug Conjugates: Modes of Toxicity Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Melissa M. Schutten, DVM, PhD, DACVP Safety Assessment Pathology NorCal Society of Toxicology Meeting September 27, 2012

2 Overview Introduction to Antibody Drug Conjugates (ADCs)
Modes of ADC toxicity Challenges associated with nonclinical safety evaluation of ADCs Summary I’ll begin todays talk with a general introduction to ADCs, including their anatomy, rationale for their design/existence,their benefit over traditional chemotherapy and mechanism of action- we’ll then transition to their modes of toxicity- talking specifically about the unique ways that ADCs can cause toxicity. I’ll touch briefly on the current and future challenges associated with ADC safety evaluation and then summarize what we learned.

3 Anatomy of an Antibody-Drug Conjugate (ADC)
Linker stable in circulation Antibody targeted to tumor Linker biochemistry Acid labile (hydrazone) Enzyme dipeptides (cleavable) Thioether (uncleavable) Hindered disulfide (uncleavable) Site of conjugation Fc, HC, LC Humanized monoclonal Ab (IgG1) mAb with Fc modifications (modulate ADCC, CDC activity) Other mAb fragments Very potent chemotherapeutic drug Antibody drug conjugates are a unique type of therapeutic agent that is a hybrid of a large molecule and small molecule. ADCs consist of an antibody targeted to a tumor antigen attached to a highly potent cytotoxic drug by means of relatively stable linker. Antbody: The type of antibody used in ADCs are usually IgG1. This particular class of antibody can trigger antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In the context of an Adc, modulation of the Fc portion of the mAb may be desirable to alter the ability of the antibody to trigger ADCC or CDC immune responses, since this type of activity may not be desirable to the efficacy or safety of conjugate. In addition, modulation of the Fc portion may be desirable to inhibit triggering of a specific signaling cascade. An alternative to using a full length or Fc modulated Ab in ADCs, is to use a fragments of the mAb (such as Fabs). Cytotoxin: A number of different classes of cytotoxins are available for the treatment of cancer. These drugs target rapidly proliferating cells by disrupting different aspects of cellular proliferation, inluding DNA replication, repair, translation, and cell division. Because cancer cells have a higher rate of cell proliferation than normal cells, cancer cells are more susceptible to cytotoxic effects of these drugs; however it should be noted that the cytotoxins are not specific for cancer cells. The cytotoxins commonly used in ADCs fall into two categories: those that target microtubules (tubulin polymerization inhibitors) and DNA damaging agents. The maytansines (DM1) and the auristatins(MMAE) are compounds that inhibit microtubule assembly. The maytansines and their derivatives were discovered in the early 1970s and were shown to be 100 to 1000-fold more potent than other microtubule inhibitors such as vinblastine. Similarly, auristatins (MMAE) which are synthetic analogs of dolastatin, have been shown to be 50 to 200-fold more potent than doxorubicin. Aside from high potency, other desirable characteristics of a cytotoxin suitable for ADCs are good solubility and stability in aqueous soltions, low MW, accessibility of reactive groups for conjugation and low immunogenicity. Linker: the linker is a critical part of the multicomponent ADC. There are generally two classes of linkers based on their biochemistry; cleavable and uncleavable. Acid labile linkers undergo hydrolysis in the acidic environment (associated with non-specific release of the drug in clinical studies); peptide-based linkers which utilize a peptide bond to link the Ab to drug and undergo hydrolysis by intracellular lysosomal proteases. Hindered disulfide linkers are selectively cleaved in the cytosol due to high intracellular concentrations of glutathione The class of thioether linkers if noncleavable and drug is likely released by intracellular proteolytic degradation. So, what’s the benefit for using such as complex multicomponent therapeutic compound to treat cancer? Tubulin polymerization inhibitors Maytansines (DM1, DM4) Auristatins (MMAE, MMAF) DNA damaging agents Calicheamicins Duocarmycins Anthracyclines (doxorubicin) 3

4 Improving the Therapeutic Window
ADCs can selectively deliver a potent cytotoxic drug to tumor cells via tumor-specific and/or over-expressed antigens Increase drug delivery to tumor Reduce normal tissue drug exposure Chemotherapy ADC TOXIC DOSE (MTD) Therapeutic Window Combining a cytotoxic drug with a mAbs can provide the best of both worlds in terms of efficacy and safety. One is able to selectively deliver a highly potent cytotoxic drug to a tumor cell using the exquisitive specificity of a monoclonal ab for a particular Ag- an Ag that is either overexpressed or, preferentially, only expressed, in tumor cells. When compared to a standard chemotherapy, selectively delivering a potent cytotoxin to a tumor using an ADC allow you to deliver a much higher dose of drug to your cell of interest while effectively increasing the window b/w your toxic dose and minimally efficacious dose. So, let’s look at an example of the advantages that ADCs have over standard “chemo”: TOXIC DOSE (MTD) DRUG DOSE Therapeutic Window EFFICACIOUS DOSE (MED) EFFICACIOUS DOSE (MED) MTD: Maximum tolerated dose; MED: Minimum Efficacious Dose

5 ADC More Efficacious than Free Cytotoxin in Mice
DM1 Free DM1 (cytotoxin) In this example, we look at the demonstrated increased efficacy in mice of the adc over the free cytotocin (mimicking the ADC vs standard chemotherapy comparison) by evaluating the mean tumor volume over time in mouse tumor models (efficacy models). This study shows that dosing mice harboring a HER2 positive breast cancer xenograft treated with standard chemo/free cytotoxin, DM1 (cytotoxcin alone) vs DM1 conjugated to the a HER Ab (traztuzumab-DM1) ADC: the mean tumor volumes remain smaller for a longer period of time in the ADC treated animals vs the free drug. This implies that the ADC is more efficacious at inhibiting tumor growth in this model than in the free drug arm alone. There is much better efficacy, of course, of ADC over Ab vs. control as well. (question about traz insensitive?) T-DM1 (ADC) Parsons et al, AACR (2007); Modified from S. Spencer 5

6 ADC Better Tolerated than Free Cytotoxin in Rats
Single IV dose; rats T-DM1 (2040 µg DM1/m²) (% change from baseline) Body Weight Besides efficacy, tolerability of the drugs are a major consideration when comparing two therapeutic agents. Tolerability in tox studies are often crudely assessed by monitoring changes in body weights over time. This data speaks to the point that the ADC is better tolerated than the free cytotoxin in rats. Again, using the same T-DM1 ADC in a single IV injection, we can see that there is a dramatic decline in the body weights of animals and early mortality that were dosed with the free cytotoxin (DM1) in comparison to little- no impact on the body weights of rats dosed with the ADC. In fact, TDM1 dosed rats continue to gain weight after the initial dose. (does this bind to rat?) Free DM1 (2400 µg DM1/m²) Early mortality (100%) Time (Day) 6 T-DM1: Trastuzumab emtansine 6

7 ADC Better Tolerated than Free Cytotoxin in Monkeys
6 mg/kg ADC (~750 μg MMAE/m2) 0.063 mg/kg MMAE (~750 μg MMAE/m2) White Blood Cells In addition to monitoring body weights of animals dosed with ADCs, tolerability and toxicity is often assessed by clinical pathology parameters; such as hematology and clinical chemistries. These are sensitive markers of organ toxicity. In our experience with ADCs at Genentech, we’ve identified a suite of organ toxicities typical of ADCs. As mentioned previously when introducing ADC anatomy, these cytotoxins often damage rapidly proliferating cells in the body; as such bone marrow (in particular neutrophils and/or platelets), lymphoid organs such as lymph nodes, thymus and spleen, testes are mainly affected. There are variable effects on the GI tract (crypts) and possible liver and kidney tox-dependent on the cytotoxin. So, in this example, we monitored mean neutrophil count as a marker of toxicity in NHPs after single IV injections of either an ADC and or free drug. Animals treated with the ADC demonstrated no real impact on their neutrophil counts whereas animals treated with the free drug have sharp decline in neuts at ~7-8 days post dose; consistent with a neutrophil “hit” and deecrease in neutrophil count. This indicates that the ADC has been tolerated better than the free drug and has less evidence of systemic hematologic toxicity. So how do these ADCs effect their cytotoxicity on the cells of interest? No neutrophil decreases when cytotoxic drug delivered linked to an antibody ~2-3 times more cytotoxic drug can be given as an ADC A. Kim, D. Danilenko, N. Dybdal, K. Flagella, K. Achilles-Poon

8 Modes of Anti-tumor Activity of ADCs
Tumor Cells Tumor Cell Tumor cytotoxicity is target-enhanced (bystander effect) ADC-Ag binding → extracellular cleavage of toxin → release of toxin in local tumor environment → diffusion of toxin intracellularly to neighboring tumor cells → tumor cell death The mechanism of anti-tumor activity of an ADC can be two fold: target-directed and target-enhanced (or secondary to the bystander effect). An ADC can selectively bind to an antigen on the cell surface of a tumor cell, internalized in the lyzosome, degraded and the cytoxin released from the Ab intracellularly. The other mechnism that an ADC can bind to the Ag, extracellular cleavage of the toxin may occur and release of toxin in the local environment may diffuse into the neighboring cell causing cytotoxicity. A highly charged metabolite may be hindered from free difuse through a lipid membrane- and judicious use of a linkers may be valuable in manipulating the bystander killing effect. The antigen is highly important in the specificity of the target-directed tumor cytotoxicity and bears a bit of attention before moving on to the modes of toxicity of ADCs. Tumor cytotoxicity is target-directed ADC-Ag binding → internalization in lysosomes → ADC degradation → release of toxin intracellularly → tumor cell death 8

9 Tissue Antigen Characteristics Are Key in ADCs
Careful selection of target antigens are an important criterion for both the safety and efficacy of an ADC The ‘ideal’ tissue antigen should have: High level of target expression in cancer cells Little to no expression in normal cells Expressed on the cell surface Readily internalized No shedding into the blood by cleavage of the antigen from cancer cell surface The number of antigen molecules and antibody binding affinity for the antigen may affect the potency of the ADC Careful selection of target antigens are an important criterion for both the safety and efficacy of an ADC. The ideal tissue antigen should be be expressed in high levels on cancer cells (both the primary tumor and the metastatic tumor) and ideally not on normal cells; but in the real world, may have decreased of limited expression on normal cells. The ag should be expressed on the cell surface allowing for Ab binding and should be readily internalized- since the MOA of ADCs relies on internalization of the ADC after binding. Ideally, the ag should not be shed by cleavage from cancer cells b/c one would want to avoid ADC binding and systemic cytotox. The binding affinity of the Ab and number of AG molecules on the cell surface also likely impact the ADC efficacy. However, a clear correlation between antigen expression and sensitivity to the therapeutic mAb has not been shown.

10 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) So, let’s talk in more depth about the modes of toxicity of ADCs. ADCs can cause toxicity by either systemic release of the toxin or by unwanted ADC-mediated cytotxicity. (Speak each type of sub bullet) We will consider each of these subcategories in more details now: 10

11 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) I mentioned before when introducing you to the anatomy of ADCs that the linker is a critical component to the stability of the overall structure. Instability of the linker can result in release of the cytotoxin at an undesirable time or in an undesirable environment. The impact of linker stability of the toxicity profile was investigated in greater depth with Genentech’s CD22 ADC program. 11 11

12 Slower Drug Deconjugation With Uncleavable Linker
Single IV dose 20 mg/kg ADC Days post dose Concentration (µg/ml) Total Ab Uncleavable linker To investigate the impact of linker stability on the release of drug and systemic toxicity, various linker-drug combinations that all result in the release of cytotoxic metabolites , were dosed to rats and the PK and tolerability/toxicity was assessed. In this study, the investigators used maytansinoid linker-drugs consisting of the maytansine DM1 with one of two different linkers: a disulfide linker SPP(which will release drug through the reduction of the sulfide bond) or the thioether linker MCC (which is uncleavable such that the Ab must be degraded to release the drug. (Two other ADCs used in these experiements and I’ll speak to those on the next slide: They are based on the auristatins: the cytotoxin MMAE linked to Ab cysteines by MC-vc-PAB and cleaved internally by cathepsin B In contrast MC-MMAF are uncleavable and must be internalized and degraded within the cell. In this study, female SD rats were given a single IV dose of one of the 4 linker-drug combinations conjugated to CD22 (matched at 20 mg/kg ADC- highest tolerated dose for DM1).The CD22 mAb does not bind rats and so the results should reflect systemic toxicity of the ADC in general rather than the effects of targeting the ADC to specific tissues. In examining the PK curves from animals treated with the cleavable vs. noncleavable linker drug conjugates; total Ab clearance (measured by ELISA) was similar for both cleavable and uncleavable conjugates suggesting that the type of linker has a minimal effect on the metabolism of the Ab. However: whereas the drug-loaded uncleavable linker conjugates (measured by ???) cleared with similar kinetics as the total ab, the cleavable linker conjugates lost drug more quickly (SPP-DM1). This suggests that the cleavable linker ADCs release more free drug into the circulation. Given that there was no detectable differences in the clearance rates of the total Abs and that there it appears that the ADC cleavable linker releases more drug(deconjugates) faster than the noncleavable llinker drug conjugate in systemic circulation, the authors hypothesized that the ADCs with uncleavable linkers (MCC-DM1 and MC-MMAF, may be better tolerated because they released smalerl amounts of free drug or small molecule metabolites into systemic circulation: Cleavable linker Polson, et al., Cancer Res., 69(6), 2009

13 More Stable Linker Reduces Systemic Toxicity of ADC in Rats
Single IV dose given on Day 1 : Change in bodyweight (grams) Days post dose CD22-DM1 with cleavable linker Looking first the the body weight data as a measure of tolerability: Only the CD22-SPP-DM1 had a negative effect on body weight. Polson, et al., Cancer Res., 69(6), 2009

14 More Stable Linker Reduces Systemic Toxicity of ADC in Rats
Single IV dose given on Day 1 : Explain the hem and chem changes in the cleavable linkers over uncleavable linkers vs. control. In these studies, ADCs with uncleavable linkers showed no significant hematologic effects, minimal impact on body weights and slower deconjugation or loss of drug from the ADC: suggesting that they are much better tolerated than the ADCs with cleavable linkers due to their relatively stability of the drug on Ab, limiting the release into systemic circulation. . Polson, et al., Cancer Res., 69(6), 2009

15 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC DAR Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) The next mode that ADC can cause toxicity is through catabolism or breakdown of the ADC.A Breakdown the ADC itself can result in the generation of various fragments/components of the ADC; including the liberation of free drug from the Ab. One of the important factors that will impact an ADCs toxicity is the number of drugs per antibody or the DAR. 15

16 Early Observation: Highly Drugged ADCs More Toxic
DAR: Drug-to-Antibody Ratio DAR 2 DAR 4 DAR 6 DAR 2 DAR 4 DAR 6 An early observation in ADCs was that conventional Ab drug conjugation processes resulted in a heteorgenous species with variable numbers of drugs conjugated to the Ab- DAR ranging from Its important to remember that even when you have a lot of ADC with an average DAR of 3, there can still be substantial variability in the species of ADC with DARs from 0-6 or more. Bioanalytical assays are an important component of assessing the DAR of these ADC species and at Genentech, the standard assay paradigm involves a total AB assay (capturing the Ab by ELISA) and a LC-MS assay that measures the mass differences in these complex ADC species: this way one can get a sense of the average DAR in a lot with accuracy. Having a high proportion of these highly drugged Abs in your mixture was concerning in terms of toxicity higher DAR species were suspected to be potentially more toxic. To investigate this, a single dose IV toxicity studies using Herceptin-MMAF with a cleavable linker to evaluate the effects of variable DAR on rats showed decreased tolerabilities based on body weight effects and elevations in AST in rats treated with increasing DAR ratios. (Does herceptin bind in rats?????) Explain the graph on tolerabiltity and the graph on increasing DAR and increased AST elevations at matched ug/m2 MMAE. The higher DAR species were associated with faster in vivo clearance and increased toxicity.

17 ThioMAb Technology: Controlling Heterogeneity
Proportion ADC DAR Proportion TDC In an effort to retain the in vivo efficacy of a conventional ADC and control the variability of the DAR, thiomab engineering technology was developed at genentech. This allowed for more homogenous drug load and elimination of a highly drugged ADC (High DAR) that may be more toxic. Talk about the engineering differences between an ADC vs TDC (engineered cysteines on the TDC that allow for controlled stoichemetry) and illustration of the DAR differences- in particular make the point about elimination of the highly drugged species. Efficacy studies demonstrated that a TDC was of equivalent efficacy as the ADC when you compare a mg/kg basis of ADC/TDC. However, looking at efficacy from a matched cytotoxin dose (MMAE), the TDC is actually twice as efficacious as the ADC because you are able to deliver half the DAR compared to the ADC. In rat tox studies in which the dose of matched MMAE ug/m2 ADC vs. 16TDC at (different DAR ratio), the TDC was better tolerated than the ADC in rats (less changes of BW and Hem/chem parameters). Looking at the PK in more detail from these studies gives us a sense of how these two types of ADCs vary. DAR Engineered ThioMAb backbone allows more homogenous drug load (MMAE) Efficacy of TDC  ADC (mg/kg basis) and  2 x ADC (ug MMAE/m2 basis) Junutula, et al., Nat. Biotech., 26(8), 2008

18 Catabolism and Deconjugation of TDC is Slower than ADC in Rats
Single dose I.V. PK study: ADC or TDC with matched cytotoxin (MMAE) doses A thorough kinetic analysis using chimeric antibodies (Fig. 5b–d) showed that the total TDC is cleared somewhat more slowly than the ADC (9.5 ± 2.9 versus 16.1 ± 3.5 ml/day/kg), and the proportion of TDC still bearing at least one drug decreased substantially more slowly than the corresponding proportion of ADC (14.1 ± 3.0 versus 41.6 ± 4.8 ml/day/kg). Therefore, we conclude that despite bearing fewer drugs per antibody on average, the TDC variants retain the conjugated drugs more effectively in rats than their ADC counterparts. (((Insert rat body weight data to speak about tolerability of TDCs over ADCs))) Deconjugation of the Antibody Catabolism of the Antibody Junutula, et al., Nat. Biotech., 26(8), 2008

19 MMAE TDC is Better Tolerated Than ADC in Monkeys
Repeat IV doses of ADC or TDC, Days 1 and 23: Examining TDC vs ADC tolerability in NHPs was performed in this example. In a multidose study (Ag-dependent??) where the ADC and TDC doses were delivered to the NHP at matched MMAE ug/m2 doses (again, because there are half as many Drugs per ab on the TDC, we delivered 2x the dose on a mg/kg basis in comparison to the ADC), we monitored the impact of the neutrophils. Looking at the day 8 and day 32 neutrophil counts (~7 days post dose, when we expect that the neutrophils, if impacted by the toxin, would be depleted), we can see there is a a 2 fold difference(decrease) in the neutrophils on the ADC vs the TDC. Again, we see similar results on day 32. Examining the impact of increasing TDC doses (increased ug/m2 dose of MMAE), there are corresponding decreases in the neutrophil count. What this data tells us, is that there is little to no impact on neutrophils, a sensitive marker of MMAE-mediated toxicity, in NHPS given equivalent MMAE doses as that of the ADC in which there is a demonstrated neutropenia. No neutrophil decreases with TDC compared to equivalent ug/m2 dose of ADC Junutula, et al., Nat. Biotech., 26(8), 2008 19

20 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC DAR Site of conjugation Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) Not only does the DAR impact of the toxicity of ADCs, but also the site of drug conjugation on the Ab. 20

21 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) ADCs can cause toxicity from targeted binding to normal tissues expressing antigen 21 21

22 Target Antigen Binding Causes “On-Target” Lymphoid Depletion
B-cell target depletion in splenic follicles: An example of “exaggerated pharmacology” Anti-cyCD79b Anti-cyCD79b MCC DM1 Ki-67 Vehicle CD20 So-called “On Target” toxicity may be caused when an ADC binds an antigen on normal cells causing toxicity. This type of toxicity or evidence of pharmacologic activity is illustrated in this example: CD79B binds to B cells in the NHP was an adc developed to target non hodgkin’s lymphoma. In repeat dose NHP studies, depletion of these CD79 B cells by the CD79B ADC was noted after treatment and is illustrated in this photomicrograph of splenic follicles. In this illutstration, decreased numbers of CD20 (also a B cell marker) positive B cells occurs in the B cells of splenic lymphoid follicles with Ab and ADC. However, depletion of this b cell depletion in the ADC is due to depletion of the rapidly dividing cells in the germinal center of b cells; as evidenced by Ki67 staining. Inhibition of rapidly proliferating cells in the splenic follicle is consistent with depletion of the cells by a microtubule inhibitor- pharmacologic evidence consistent with ADC mechanism of action. Polson, et. al, Mol Cancer Ther 8(10), 2009

23 Target Toxicity to Normal Tissues
Another clinical example ofunwanted “on target” tox is with bivatuzumab is a humanized monoclonal antibody directed against CD44v6, which previously seemed to be safe in phase I radioimmunotherapy trials, whereas the conjugated mertansine is a potent maytansine derivative. Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m2 and one at the 120 mg/m2 level experienced stable disease during treatment phase but also developed grade 1 skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m2), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The risk-benefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials. Therefore, development of the conjugate was discontinued. Interindividual variability in pharmacokinetic variables was low and exposure to BIWI 1 increased proportionally with dose. No anti–bivatuzumab mertansine reactions were observed. Conclusion: The main toxicity of bivatuzumab mertansine was directed against the skin, most probably due to CD44v6 expression in this tissue. The majority of skin reactions was reversible; however, one fatal drug-related adverse event had occurred. Clinical development was discontinued before reaching maximum tolerated dose. Results: Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m2 and one at the 120 mg/m2 level experienced stable disease during treatment phase but also developed grade 1 skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m2), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The risk-benefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials. Therefore, development of the conjugate was discontinued.

24 Modes of Toxicity of ADCs
+ Normal Cell Systemic release of toxin Instability of linker Catabolism of ADC Unwanted ADC-mediated cytotoxicity Targeted binding to normal tissues expressing antigen Off-target (cross reactive) binding to normal tissues Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) Unwanted-mediated cytotox can also occur because of off-target (cross-reactive) binding to normal tissues and non-Ag mediated ADC uptake (pinocytosis,etc….) Talk a little bit more about these theoretical concerns? 24 24

25 Summary An ADC is both a “large molecule” and a “small molecule”.
ADCs hold great promise for improving current oncology therapies. Highly potent cytotoxic agents are delivered directly to cancer cells, sparing normal tissues. ADCs tend to be better tolerated than standard chemotherapy. Increased therapeutic window allows for better balance between safety/efficacy. There is a fine balance between efficacy and toxicity. Choice of linker, cytotoxic drug and mAb are all important determinants of safety, PK, and efficacy. Toxicity is usually antigen-independent, ADC/drug-dependent. Linker stability, DAR, and site of drug conjugation impacts toxicity.

26 Acknowledgements Luna Liu Andy Boswell Helen Davis Margaret Kenrick
Reina Fuji Kelly Flagella Willy Solis Kirsten Achilles-Poon Jacqueline Tarrant Rama Pai Ning Ma Joe Beyer Trung Nguyen Nghi La Fiona Zhong Michelle McDowell Noel Dybdal Donna Dambach Theresa Reynolds Angela Hendricks Amy Oldendorp Surinder Kaur Ben Shen Jay Tibbitts Joo-Hee Yi Kedan Lin Doug Leipold Ola Saad Montserrat Carrasco-Triguero Keyang Xu Luna Liu Andy Boswell Helen Davis Margaret Kenrick Susan Spencer Paul Polakis Bonnee Rubinfeld Jagath Junutula Shang-Fan Yu David Kan Ivan Inigo Wai Lee Wong Kathy Kozak Elaine Mai Jeff Gorrell Michael Mamounas Andrew Polson Seattle Genetics


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